US20170327503A1

US20170327503A1 - Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases

Info

Publication number: US20170327503A1
Application number: US15/501,233
Authority: US
Inventors: Sanne Schrøder Glad; Kim Birkebaek Jensen; Niels Grøn NØRAGER; Ian SARVARY; Mikkel VESTERGAARD; Alex Haahr Gouliaev; Lene Teuber; Luigi Piero Stasi
Original assignee: Nuevolution AS
Current assignee: Nuevolution AS
Priority date: 2014-08-04
Filing date: 2015-07-31
Publication date: 2017-11-16
Anticipated expiration: 2035-07-31
Also published as: MY195016A; JP6604664B2; IL250325B; EP3177611A1; NZ766530A; LT3177612T; EP3177612B1; SI3177612T1; EP3177611B1; IL250325A0; MX2017001553A; BR112017002214B1; CN106661002B; US20200392140A1; KR102523430B1; MY194204A; CL2017000270A1; NZ729137A; MA40552A; AU2015299149B2

Abstract

Disclosed are compounds active towards nuclear receptors, pharmaceutical compositions containing the compounds and use of the compounds in therapy.

Description

FIELD

Aspects and embodiments described herein relate to compounds active towards nuclear receptors, pharmaceutical compositions comprising the compounds, and methods of treating inflammatory, metabolic, oncologic and autoimmune diseases or disorders using the compounds.

BACKGROUND

Nuclear receptors are a family of transcription factors involved in the regulation of physiological functions, such as cell differentiation, embryonic development, and organ physiology. Nuclear receptors have also been identified as important pathological regulators in diseases such as cancer, diabetes, and autoimmune disorders.
Examples of nuclear receptors include the nuclear retinoic acid receptor-related orphan receptors (RORs). RORs contain four principal domains: an N-terminal A/B domain, a DNA-binding domain, a hinge domain and a ligand binding domain. Binding of ligands to the ligand-binding domain is believed to cause conformational changes in the domain resulting in downstream actions. Different isoforms exist and these isoforms differ in their N-terminal A/B domain only.
RORs consist of three members, namely ROR alpha (RORα), ROR beta (RORβ) and ROR gamma (RORγ or RORc).
RORα is expressed in many tissues such as cerebellar Purkinje cells, the liver, thymus, skeletal muscle, skin, lung, adipose tissue and kidney.
RORγ also has a broad expression pattern and was the most recently discovered of the three members. To date, five splice variants have been recorded for RORγ coding for two different protein isoforms: RORγ1 and RORγ2 (RORγ2 is also known as RORγt). Generally RORγ is used to describe RORγ1 and/or RORγt. RORγ1 is expressed in many tissues and is predominantly expressed in the kidneys, liver, and skeletal muscle. In contrast, expression of RORγt is restricted to lymphoid organs such as the thymus. RORγt has been identified as a key regulator of Th17 cell differentiation. Th17 cells are a subset of T helper cells which preferentially produce the cytokines IL-17A, IL-17F, IL-21 and IL-22. Th17 cells and their products have been shown to be associated with the pathology of many human inflammatory and autoimmune disorders.
There is thus evidence that RORα and RORγ play a role in the pathogenesis of many diseases.
It would be desirable to provide compounds that modulate the activity of RORα and/or RORγ for use in treating inflammatory, metabolic and autoimmune diseases.

SUMMARY

In one aspect provided herein are compounds of Formula (I)
or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and stereoisomers thereof, wherein:
Y is NR or O;
R is hydrogen or substituted or unsubstituted C_1-4alkyl;
R₁is selected from the group consisting of hydrogen, —OH, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, and substituted or unsubstituted C_2-4alkenyl;
R₂is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, —CN, and —OH;
or R and R₂are combined to form a substituted or unsubstituted fused ring;
R₃is selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, oxo, —C(═O)R₁₀;
R_4ais selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C_1-6alkyl;
R_4bis selected from the group consisting of hydrogen, halogen, oxo, —OH, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, and —C(═O)R₁₀;
R₅is selected from the group consisting of —(CR₈R₉)pOR₁₂, —(CR₈R₉)p-CR₁₃R₁₄R₁₅, —(CR₈R₉)p-C(═O)OR₇, and —(CR₈R₉)p-C(═O)NR₈R₉;
n, m, and p are integers independently selected from the group consisting of 0, 1, 2, 3 and 4;
R_6a, R_6bare independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_2-6alkynyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_1-6heteroalkyl, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R_6aand R_6bare taken together to form an oxo group or a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl, or R_6aand R₁₃are taken together to form a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-5heteroalicyclyl;
R₇, R₈, R₉, and R₁₂, are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl;
R₁₀is selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, —OH, —NH₂, —NH(C_1-6alkyl), —N(C_1-6alkyl)₂, and C_3-7cycloalkyl;
R₁₃is absent, or selected from the group consisting of hydrogen, —OH, —CN substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, and —(CR₈R₉)p-C(═O)OR₇, —(CR₈R₉)p-SO₂R₇and —(CR₈R₉)p-C(═O)NR₈R₉;
R₁₄and R₁₅are independently selected from the group consisting of hydrogen, and substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl; or
R₁₄and R₁₅are combined to form a ring system selected from the group consisting of substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic heteroalicyclyl, provided that it is not 5,6-dichloro-1H-benzo[d]imidazol-2-yl when R₁and R₂both are hydrogen;
C is a ring system selected from C_2-9heteroalicyclyl;
wherein B is attached to a carbon atom adjacent the N atom of ring system C; and
with the proviso the compound is not:
According to a further aspect, R and R₂are combined to form a fused ring. In another aspect, R₅is —(CR₈R₉)p-C(═O)OR₇, or —(CR₈R₉)p-C(═O)NR₈R₉. Alternatively, R₅is —(CR₈R₉)p-CR₁₃R₁₄R₁₅wherein R₁₄and R₁₅are combined to form a ring system.
According to another aspect, there is provided a pharmaceutical composition comprising a compound of the herein above described type and at least one pharmaceutical acceptable excipient.
According to yet another aspect, the herein above described compound or pharmaceutical composition are for use in therapy.
According to another aspect, the herein above described compound or pharmaceutical composition are for use in the treatment and/or prevention of inflammatory, metabolic and autoimmune diseases or disorders.
In another aspect, the herein above described compound or pharmaceutical composition are for modulating the activity of a retinoic acid receptor-related orphan receptor (ROR).
Further, advantageous features of various embodiments are defined in the dependent claims and within the detailed description below.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
As used herein, any “R” group(s) such as, without limitation, R₁, R₂, R₃, R₄, R₅, R₈, R₉, and R₁₀, represent substituents that can be attached to the indicated atom. A non-limiting list of R groups includes but is not limited to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl. If two “R” groups are covalently bonded to the same atom or to adjacent atoms, then they may be “taken together” or “combined” as defined herein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group. For example, without limitation, if R_aand R_bof an NR_aR_bgroup are indicated to be “taken together” or “combined”, it means that they are covalently bonded to one another at their terminal atoms to form a ring that includes the nitrogen:
As readily recognized by the skilled person, any given group disclosed herein may comprise further hydrogen(s) than the one(s) provided by a R-group, being hydrogen, attached to the group.
Whenever a group is described as being “unsubstituted or substituted,” if substituted, the substituent(s) (which may be present one or more times, such as 1, 2, 3 or 4 times) are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
When a substituent on a group is deemed to be “substituted,” the substitutent itself is substituted with one or more of the indicated substitutents. When the referenced substituent is substituted, it is meant that one or more hydrogen atoms on the referenced substituent may be replaced with a group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references Greene and Wuts, Protective Groups in Organic Synthesis, 3^rdEd., John Wiley & Sons, New York, N.Y., 1999, which is hereby incorporated by reference in its entirety.
As used herein, “C_mto C_n,” “C_m-C_n” or “C_m-n” in which “m” and “n” are integers refers to the number of carbon atoms in the relevant group. That is, the group can contain from “m” to “n”, inclusive, carbon atoms. Thus, for example, a “C₁to C₆alkyl” group refers to all alkyl groups having from 1 to 6 carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)—, CH₃CH(CH)₃CH₂—, CH₃CH(CH)₃CH₂— and (CH₃)₃C—. If no “m” and “n” are designated with regard to a group, the broadest range described in these definitions is to be assumed.
As used herein, “alkyl” refers to a straight or branched hydrocarbon chain group that is fully saturated (no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms, such as “C_1-6”. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compounds may be designated as “C₁-C₄alkyl,” “C_1-4alkyl” or similar designations. By way of example only, “C₁-C₄alkyl” or “C_1-4alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. If more than one double bond is present, the double bonds may be conjugated or not conjugated. The alkenyl group may have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as “2 to 20” refers to each integer in the given range; e.g., “2 to 20 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated). When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, haloalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as “2 to 20” refers to each integer in the given range; e.g., “2 to 20 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated). An alkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkenyl group substitution.
As used herein, “hetero” may be attached to a group and refers to one or more carbon atom(s) and the associated hydrogen atom(s) in the attached group have been independently replaced with the same or different heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur.
As used herein, “heteroalkyl,” by itself or in combination with another term, refers to a straight or branched alkyl group consisting of the stated number of carbon atoms, where one or more carbon atom(s), such as 1, 2, 3 or 4 carbon atom(s), and the associated hydrogen atom(s) have been independently replaced with the same or different heteroatoms selected from nitrogen, oxygen and sulfur. The carbon atom(s) being replace may be in the middle or at the end of the alkyl group. Examples of heteroalkyl include, but are not limited to, —S-alkyl, —O-alkyl, —NH-alkyl, -alkylene-O-alkyl, etc
As used herein, “aryl” refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. When substituted, substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), in which at least one of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. Examples of monocyclic “heteroaryl” include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazole, and triazine. Examples of multicyclic “heteroaryl” include, but are not limited to, quinoline, isoquinoline, quinazoline, quinoxaline, indole, purines, benzofuran, benzothiophene, benzopyranones (e.g. coumarin, chromone, and isocoumarin). A heteroaryl may be substituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. When substituted, substituents on a heteroayl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
An “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group. The alkylene and aryl group of an aralkyl may be substituted. Examples include but are not limited to benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group.
A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. The alkylene and heteroaryl group of heteroaralkyl may be substituted. Examples include but are not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl and imidazolylalkyl, and their substituted as well as benzo-fused analogs. In some cases, the alkylene group is a lower alkylene group.
An “alkylene” is a straight-chained tethering group, forming bonds to connect molecular fragments via their terminal carbon atoms. The alkylene may have 1 to 20 carbon atoms. The alkylene may also be a medium size alkylene having 1 to 10 carbon atoms, such as “C_1-6” The alkylene could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene may be designated as “C₁-C₄alkylene”, “C_1-4alkylene” or similar designations. Non-limiting examples include, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), and butylene (—(CH₂)₄—) groups. In the case of methylene, the two connected fragments are connected to the same carbon atom. A lower alkylene group may be substituted.
As used herein, “heteroalkylene” by itself or in combination with another term refers to an alkylene group consisting of the stated number of carbon atoms in which one or more of the carbon atoms, such as 1, 2, 3 or 4 carbon atom(s), are independently replaced with the same or different heteroatoms selected from oxygen, sulfur and nitrogen. Examples of heteroalkylene include, but not limited to —CH₂—O—, —CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—, —CH₂—NH—, —CH₂—CH₂—NH—, —CH₂—CH₂—CH₂—NH—, —CH₂—CH₂—NH—CH₂—, —O—CH₂—CH₂—O—CH₂—CH₂—O—, —O—CH₂—CH₂—O—CH₂—CH₂—, and the like.
As used herein, “alkylidene” refers to a divalent group, such as ═CR′R″, which is attached to one carbon of another group, forming a double bond. Alkylidene groups include, but are not limited to, methylidene (═CH₂) and ethylidene (═CHCH₃). As used herein, “arylalkylidene” refers to an alkylidene group in which either R′ or R″ is an aryl group. An alkylidene group may be substituted.
As used herein, “alkoxy” refers to the group —OR wherein R is an alkyl, e.g. methoxy, ethoxy, n-propoxy, cyclopropoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like. An alkoxy may be substituted.
As used herein, “alkylthio” refers to the formula —SR wherein R is an alkyl is defined as above, e.g. methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, and the like. An alkylthio may be substituted.
As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in which R is an aryl as defined above, e.g., phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio and the like. Both an aryloxy and arylthio may be substituted.
As used herein, “alkenyloxy” refers to the formula —OR wherein R is an alkenyl as defined above, e.g., vinyloxy, propenyloxy, n-butenyloxy, iso-butenyloxy, sec-pentenyloxy, tert-pentenyloxy, and the like. The alkenyloxy may be substituted.
As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted.
As used herein, “cycloalkyl” refers to a completely saturated (no double bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups may range from C₃to C₁₀, such as from C₃to C₆. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated. When substituted, substituents on a cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including an aryl and a heteroaryl.
As used herein, “cycloalkenyl” refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro-connected fashion. Cycloalkenyl groups may range from C₃to C₁₀, such as from C₅to C₁₀. A cycloalkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated. When substituted, substituents on a cycloalkenyl group may form an aromatic ring fused to the cycloalkenyl group, including an aryl and a heteroaryl.
As used herein, “cycloalkynyl” refers to a cycloalkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkynyl groups may range from C₈to C₁₂. A cycloalkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated. When substituted, substituents on a cycloalkynyl group may form an aromatic ring fused to the cycloalkynyl group, including an aryl and a heteroaryl.
As used herein, “heteroalicyclic” or “heteroalicyclyl” refers to a 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The heteroalicyclic or heteroalicyclyl groups may range from C₂to C₁₀, in some embodiments it may range from C₂to C₉, and in other embodiments it may range from C₂to C₈. The “heteroalicyclic” or “heteroalicyclyl” may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro-connected fashion; and the nitrogen, carbon and sulfur atoms in the “heteroalicyclic” or “heteroalicyclyl” may be oxidized; the nitrogen may be quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system throughout all the rings, examples are 2H-benzo[b][1,4]oxazin-3(4H)-one, 3,4-dihydroquinolin-2(1H)-one, 1,2,3,4-tetrahydroquino line, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydro-1H-benzo[d]imidazole, indoline, and 1,3-dihydro-2H-benzo[d]imidazol-2-one, and benzo[d]oxazol-2(3H)-one. Heteroalicyclyl groups may be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Examples of such “heteroalicyclic” or “heteroalicyclyl” include but are not limited to, azepinyl, dioxolanyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. When substituted, substituents on a heteroalicyclyl group may form an aromatic ring fused to the heteroalicyclyl group, including an aryl and a heteroaryl.
A “(cycloalkyl)alkyl” is a cycloalkyl group connected, as a substituent, via an alkylene group. The alkylene and cycloalkyl of a (cycloalkyl)alkyl may be substituted. Examples include but are not limited cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.
A “(cycloalkenyl)alkyl” is a cycloalkenyl group connected, as a substituent, via an alkylene group. The alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group.
A “(cycloalkynyl)alkyl” is a cycloalkynyl group connected, as a substituent, via an alkylene group. The alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group.
As used herein, “halo” or “halogen” refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).
As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. A haloalkyl may be substituted.
As used herein, “haloalkoxy” refers to a RO-group in which R is a haloalkyl group. Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and 1-chloro-2-fluoromethoxy, 2-fluoroisobutyoxy. A haloalkoxy may be substituted.
An “O-carboxy” group refers to a “RC(═O)O—” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An O-carboxy may be substituted.
A “C-carboxy” group refers to a “—C(═O)OR” group in which R can be the same as defined with respect to O-carboxy. A C-carboxy may be substituted.
A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group” wherein X is a halogen.
A dashed bond,
, represents an optional unsaturation between the atoms forming the bond. This bond may be unsaturated (e.g. C═C, C═N, C═O) or saturated (e.g. C—C, C—N, C—O). When a dashed bond is present in a ring system it may form part of an aromatic ring system.
A “nitro” group refers to a “—NO₂” group
A “cyano” group refers to a “—CN” group.
A “cyanato” group refers to an “—OCN” group.
An “isocyanato” group refers to a “—NCO” group.
A “thiocyanato” group refers to a “—SCN” group.
A “carbonyl” group refers to a “—C(═O)—” group.
A “thiocarbonyl” group refers to a “—C(═S)—” group.
An “oxo” group refers to a “═O” group.
A “hydroxy” group or “hydroxyl” group refers to an “—OH” group.
An “isothiocyanato” group refers to an “—NCS” group.
A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be the same as defined with respect to O-carboxy. A sulfinyl may be substituted.
A “sulfonyl” group refers to an “SO₂R” group in which R can be the same as defined with respect to O-carboxy. A sulfonyl may be substituted.
An “S-sulfonamido” group refers to a “—SO₂NR_AR_B” group in which R_Aand R_Bindependently of each other can be the same as defined with respect to the R group as defined for O-carboxy, or combined to form a ring system selected from the group consisting of substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. A S-sulfonamido may be substituted.
An “N-sulfonamido” group refers to a “RSO₂N(R_A)—” group in which R and R_Aindependently of each other can be the same as defined with respect to the R group as defined for O-carboxy. An N-sulfonamido may be substituted.
A “trihalomethanesulfonamido” group refers to an “X₃CSO₂N(R)—” group with X as halogen and R can be the same as defined with respect to O-carboxy. A trihalomethanesulfonamido may be substituted.
A “C-amido” group refers to a “—C(═O)NR_AR_B” group in which R_Aand R_Bindependently of each other can be the same as defined with respect to the R group as defined for O-carboxy, or combined to form a ring system selected from the group consisting of substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. A C-amido may be substituted.
An “N-amido” group refers to a “RC(═O)NR_A—” group in which R and R_Aindependently of each other can be the same as defined with respect to the R group as defined for O-carboxy. An N-amido may be substituted.
An “ester” refers to a “—C(═O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester may be substituted.
A lower alkoxyalkyl refers to an alkoxy group connected via a lower alkylene group. A lower alkoxyalkyl may be substituted.
An “amine” or “amino” refers to “RNH₂” (a primary amine), “R₂NH” (a secondary amine), “R₃N” (a tertiary amine). An amino group may be substituted.
A lower aminoalkyl refers to an amino group connected via a lower alkylene group. A lower aminoalkyl may be substituted.
Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3^rdEd., John Wiley & Sons, New York, N.Y., 1999).
As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).
As employed herein, the following terms have their accepted meaning in the chemical literature.
CDCl₃deuterated chloroform
DCM dichloromethane or CH₂Cl₂
DIPEA N,N-diisopropylethylamine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
EtOAc ethyl acetate
h hour(s)
MeOH methanol
TFA trifluoroacetic acid
It is understood that, in any compound disclosed herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enatiomerically pure or be stereoisomeric mixtures. Further, compounds provided herein may be scalemic mixtures. In addition, it is understood that in any compound having one or more double bond(s) generating geometrical isomers that can be defined as E or Z each double bond may independently be E or Z or a mixture thereof. Likewise, all tautomeric forms are also intended to be included.
As used herein, “tautomer” and “tautomeric” refer to alternate forms of a compound disclosed herein that differ in the position of a proton. Non-limiting examples include enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring —NH— moiety and a ring ═N— moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
It is understood that isotopes may be present in the compounds described herein. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound described herein a hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Base-formed salts include, without limitation, ammonium salt (NH₄ ⁺); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, piperidine, piperazine, methylpiperazine, N-methyl-D-glucamine, diethylamine, ethylenediamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine. Useful acid-based salts include, without limitation, acetates, adipates, aspartates, ascorbates, benzoates, butyrates, caparate, caproate, caprylate, camsylates, citrates, decanoates, formates, fumarates, gluconates, glutarate, glycolates, hexanoates, laurates, lactates, maleates, nitrates, oleates, oxalates, octanoates, propanoates, palmitates, phosphates, sebacates, succinates, stearates, sulfates, sulfonates, such as methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, tartrates, and tosylates.
Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
As used herein, a “prodrug” refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have better solubility than the active parent drug in pharmaceutical compositions. An example, without limitation, of a prodrug would be a compound disclosed herein, which is administered as an ester (the “prodrug”) to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to release the active parent compound. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g. Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
“Anti-drug” refers to a compound or composition acting against or opposing illicit drugs or their use. Compounds of the present application may act as anti-drugs.
As used herein, to “modulate” the activity of a receptor means either to activate it, i.e., to increase its cellular function over the base level measured in the particular environment in which it is found, or deactivate it, i.e., decrease its cellular function to less than the measured base level in the environment in which it is found and/or render it unable to perform its cellular function at all, even in the presence of a natural binding partner. A natural binding partner is an endogenous molecule that is an agonist for the receptor.
An “agonist” is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
As used herein, “partial agonist” refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with the receptor even if a large number of receptors are occupied by the compound.
An “inverse agonist” is defined as a compound, which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity.
As used herein, “antagonist” refers to a compound that binds to a receptor to form a complex that does not give rise to any response, as if the receptor was unoccupied. An antagonist attenuates the action of an agonist on a receptor. An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as birds, fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
As used herein, a “patient” refers to a subject that is being treated by a medical professional such as an M.D. or a D.V.M. to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.
A “receptor” is intended to include any molecule present inside or on the surface of a cell that may affect cellular physiology when it is inhibited or stimulated by a ligand. Typically, a receptor comprises an extracellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding (“signal transduction”). A receptor also includes any intracellular molecule that in response to ligation generates a signal. A receptor also includes any molecule having the characteristic structure of a receptor, but with no identifiable ligand. In addition, a receptor includes a truncated, modified, mutated receptor, or any molecule comprising partial or all of the sequences of a receptor.
“Ligand” is intended to include any substance that interacts with a receptor.
“Selective” or “selectivity” is defined as a compound's ability to generate a desired response from a particular receptor type, subtype, class or subclass while generating less or little response from other receptor types. “Selective” or “selectivity” of one or more particular subtypes of a receptor means a compound's ability to increase the activity of the subtypes while causing less, little or no increase in the activity of other subtypes.
As used herein, “coadministration” of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Coadministration means the simultaneous delivery of separate agents; the simultaneous delivery of a mixture of agents; as well as the delivery of one agent followed by delivery of a second agent or additional agents. Agents that are coadministered are typically intended to work in conjunction with each other.
The term “an effective amount” as used herein means an amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or palliation of the symptoms of the disease being treated.
When used herein, “prevent/preventing” should not be construed to mean that a condition and/or a disease never might occur again after use of a compound or pharmaceutical composition according to embodiments disclosed herein to achieve prevention. Further, the term should neither be construed to mean that a condition not might occur, at least to some extent, after such use to prevent said condition. Rather, “prevent/preventing” is intended to mean that the condition to be prevented, if occurring despite such use, will be less severe than without such use.
Compounds
According to one aspect compounds of Formula (I)
or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and stereoisomers thereof, wherein:
Y is NR or O;
R is hydrogen or substituted or unsubstituted C_1-4alkyl;
R₁is selected from the group consisting of hydrogen, —OH, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, and substituted or unsubstituted C_2-4alkenyl;
R₂is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, —CN, and —OH;
or R and R₂are combined to form a substituted or unsubstituted fused ring;
R₃is selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, oxo, —C(═O)R₁₀;
R_4ais selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C_1-6alkyl;
R_4bis selected from the group consisting of hydrogen, halogen, oxo, —OH, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, and —C(═O)R₁₀;
R₅is selected from the group consisting of —(CR₈R₉)pOR₁₂, —(CR₈R₉)p-CR₁₃R₁₄R₁₅, —(CR₈R₉)p-C(═O)OR₇, and —(CR₈R₉)p-C(═O)NR₈R₉;
n, m, and p are integers independently selected from the group consisting of 0, 1, 2, 3 and 4;
R_6a, R_6bare independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_2-6alkynyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_1-6heteroalkyl, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R_6aand R_6bare taken together to form an oxo group or a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl, or R_6aand R₁₃are taken together to form a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-5heteroalicyclyl;
R₇, R₈, R₉, and R₁₂, are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl;
R₁₀is selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, —OH, —NH₂, —NH(C_1-6alkyl), —N(C_1-6alkyl)₂, and C_3-7cycloalkyl;
R₁₃, if not to be taken together with R_6a, is absent, or selected from the group consisting of hydrogen, —OH, —CN substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, and —(CR₈R₉)p-C(═O)OR₇, —(CR₈R₉)p-SO₂R₇and —(CR₈R₉)p-C(═O)NR₈R₉;
R₁₄and R₁₅are independently selected from the group consisting of hydrogen, and substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl; or
R₁₄and R₁₅are combined to form a ring system selected from the group consisting of substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic heteroalicyclyl, provided that it is not 5,6-dichloro-1H-benzo[d]imidazol-2-yl when R₁and R₂both are hydrogen;
C is a ring system selected from C_2-9heteroalicyclyl;
wherein B is attached to a carbon atom adjacent the N atom of ring system C; and with the proviso the compound is not:
are provided.
As with any group of structurally related compounds which possess a particular utility, certain embodiments of variables of the compounds of Formula (I) may be particularly useful in their end use application.
In some embodiments of the compounds of Formula (I), R and R₂in combination with the pyrimidine ring form a ring system selected from pyrrolo[2,3-d]pyrimidine and 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine. The ring system may be pyrrolo[2,3-d]pyrimidine.
In some embodiments according to Formula (I) B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic heteroalicyclyl, provided that it is not 5,6-dichloro-1H-benzo[d]imidazole-2-yl; i.e.
In some further embodiments according to Formula (I), B is a ring system selected from the group consisting of aryl, monocyclic heteroaryl, and bicyclic heteroalicyclyl. In some embodiments of the compounds of Formula (I), R and R₂in combination with the pyrimidine ring form a pyrrolo[2,3-d]pyrimidine or 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine. The compounds of Formula (I) may also have the Formula (IIa):
wherein R_4eand R_4dare independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, and —OH. In preferred compounds of Formula (IIa), R_4eand R_4dmay be independently selected from the group consisting of hydrogen, methyl, and fluorine.
Embodiment disclosed herein below in relation to various groups, rings and substituents of compounds of Formula (I) are, as indicated, equally applicable to compounds of any one of the Formulae (IIa-IIe) provided below herein, provided that the relevant group, integer, ring and/or substituent is present in the Formula of concern, as readily appreciated by the skilled person.
According to another embodiment, the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe) as disclosed herein below, have R₅being —(CR₈R₉)p-C(═O)OR₇or —(CR₈R₉)p-C(═O)NR₈R₉, unless otherwise specified. In an alternative embodiment, the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe) have R₅being —(CR₈R₉)_pOR₁₂. In these embodiments, R₇, R₈, R₉, and R₁₂are independently selected of each other from hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted aryl-C_1-6alkyl and substituted or unsubstituted aryl. Preferred groups of R₇, R₈, R₉, and R₁₂are selected from hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, and aryl, while even more preferred groups are selected from hydrogen, methyl, ethyl and tert-butyl. The integer p is preferably selected from 0, 1 or 2. In some embodiments, p is 0.
According to yet another embodiment, R₅is —(CR₈R₉)p-CR₁₃R₁₄R₁₅. In this embodiment it is preferred that R₁₄and R₁₅are combined to form a ring system. Further, the integer “p” may be 0 (zero), or 1. While it is not intended that the ring system be particular limited, preferred ring systems are selected from the group consisting of substituted or unsubstituted C_3-7cycloalkyl, substituted or unsubstituted C_3-7cycloalkenyl, substituted or unsubstituted C_2-6heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. For example, R₁₄and R₁₅may be combined to form a ring system selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, thietanyl, pyrrolyl, pyrazolyl imidazolyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathianyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolanyl, dioxanyl, furyl, dihydrofuranyl, furazanyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dithianyl, thiopyranyl, thianyl, thienyl, oxetanyl, quinolyl, isoquinolyl, indolyl, iso-indolyl, and tetrahydrothienyl, any of which may be substituted or unsubstituted. Preferably, R₁₄and R₁₅are combined to form a ring system selected from the group consisting of cycloheptyl, cyclohexyl, cyclopentyl, dioxanyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxathianyl, phenyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, tetrazolyl, thianyl, thiazolyl, thienyl, thiomorpholinyl, thiopyryl, and triazolyl, all of which may be unsubstituted or substituted. Some embodiments relate to the ring system formed being phenyl, pyridyl, cyclopentyl, cyclohexyl, piperidyl, pyrrolidinyl, oxetanyl, and tetrahydropyranyl, all which may be substituted by (CH₂)_q(R_5a) as defined herein. Some embodiments relate to the ring system being phenyl, pyridyl, piperidinyl oxetanyl, or cyclohexyl. In embodiments wherein R₁₄and R₁₅are combined to form an aromatic ring system, R₁₃is absent.
In a further embodiment, the ring system formed by the combination of R₁₄and R₁₅is substituted with —(CH₂)q(R_5a) wherein R_5ais independently selected from the group consisting of —CH₂COOR₂₀, —CH₂CONR₂₁R₂₂, —CN, C_1-6alkyl, —CH₂-imidazolyl, —CH₂—SO₂R₂₀, —CH₂C(CH₃)₂(OR₂₀), —OCH₃, —CH₂-triazolyl, —CF₃, dimethyl substituted-imidazolyl-2,4-dione, —CH₂—SO₂NR₂₁R₂₂, morpholinyl, —C(═O)-morpholinyl, piperidyl-CH₂OR₂₀, —OCH₂-tetrahydrofuryl, piperazinonyl, piperidinyl-CONR₂₁R₂₂, —OH, —CONR₂₁R₂₂, —CH(OR₂₀)CH₃, —COOR₂₀, —CH₂-pyrrolidyl, C_1-6alkylene-OH, cyclopentyl, pyrrolidonyl, tetrazolyl, —CH₂— tetrazolyl, —CH₂OR₂₀, acyl, —SOR₂₀, —SO₂R₂₀, —COR₂₀, —NR₂₁SO₂R₂₀, —SO₂NR₂₁R₂₂, and halogen;
R₂₀, R₂₁, and R₂₂are independently of each other selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, —CN, substituted or unsubstituted C_3-6cycloalkyl, substituted or unsubstituted C_2-6heteroalicyclyl; and
q is an integer selected from 0, 1 or 2.
Of course the ring system formed by the combination of R₁₄and R₁₅may, in alternative embodiments, be substituted with groups other than —(CH₂)q(R_5a).
According to some embodiments, R₁₃is selected from the group consisting of hydrogen, —CN, CH₃, fluorine, —OH, —CH₂OH, —OCH₃, —CH₂CH₂OH, —CO₂H, —CO₂—C_1-4alkyl, —CH₂SO₂R₂₀and —CONR₈R₉wherein R₈and R₉are independently of each other selected from hydrogen, C_1-4alkyl and C_1-4aminoalkyl or R₈and R₉are combined to form a C₂-C₆heteroalicyclyl. Some embodiments relate to R₁₃taken together with R_6ato form a ring system selected from the group consisting of substituted or unsubstituted C_3-6cycloalkyl and substituted or unsubstituted C_2-5heteroalicyclyl.
According to some embodiments, R₁₃is absent or hydrogen.
In some embodiments of the compounds of Formula (I), Y is NR. Further, while R may be selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, and C_1-4hydroxyalkyl. In one embodiment R is hydrogen.
According to some embodiments, R₁is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-4alkyl, and substituted or unsubstituted C_1-4alkoxy. R₁may thus include C_1-4haloalkyl and C_1-4hydroxyalkyl groups. In some embodiments, R₁is hydrogen or CF₃.
According to some embodiments, R₂is selected from the group consisting of hydrogen, halogen, C_1-4alkyl, C_1-4haloalkyl, and C_1-4hydroxyalkyl. In some embodiments, R₂is a halogen such as fluorine.
In some embodiments, the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein may have an R₃group selected from hydrogen, halogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, oxo, C_1-4alkoxy and C_1-4haloalkoxy, unless otherwise specified. According to one embodiment R₃is selected from the group consisting of hydrogen, methyl, fluorine, chlorine and oxo. In some embodiments, R₃is hydrogen.
In some compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein the integer m is selected from 2, 3, or 4, and at least two of the R₃groups present are bound to the same atom of ring system C. This embodiment provides compounds with one or two geminally substituted atoms that are part of ring system C. In some embodiments, R₃is flouro, such as geminally arranged fluoro atoms.
According to some embodiments of the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, R_4ais selected from the group consisting of hydrogen, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C₁-C₆alkoxy, C_1-6haloalkoxy, heteroaryl and aryl. In some embodiments R_4agroups are selected from the group consisting of methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, bromine, fluorine, methoxy, ethoxy, C_1-2haloalkyl, C_1-2haloalkoxy and triazolyl. In some embodiments R_4agroups are —CF₃, —CF₂CF₃, —CHF₂, —OCF₃, —OCF₂CF₃, and —OCHF₂. In some embodiments R_4ais selected from the group consisting of isopropyl, halogen, ethoxy, CF₃, —OCF₃.
In some embodiments, wherein the ring system B is 6-membered aryl or heteroaryl, R_4ais arranged in the para- or meta-position, in relation to the carbon carrying ring system C.
According to some embodiments, R_4bis selected from hydrogen, oxo, halogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C₁-C₄alkoxy, and C_1-4haloalkoxy. In this embodiment, R_4bmay be further selected from methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, bromine, fluorine, methoxy, ethoxy, —OH, C_1-2haloalkyl, and C_1-2haloalkoxy. Examples of R_4bgroups comprise —CF₃, —CHF₂, —OCF₃, and —OCHF₂. In some embodiments R_4bis hydrogen.
Some embodiments relate to R_4abeing selected from the group consisting of methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, bromine, fluorine, methoxy, ethoxy, C_1-2haloalkyl, C_1-2haloalkoxy, and triazolyl arranged in the above mentioned para- or meta-position, and R_4bbeing hydrogen.
In some embodiments of the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, R_6ais selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, and substituted or unsubstituted aryl, or R_6aand R₁₃are taken together to form a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl. Further examples of R_6aare selected from hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, and aryl. It is preferred however, that R_6ais hydrogen.
According to some embodiments, R_6bis selected from hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted C_2-9heteroalicyclyl-C_1-6alkyl, and substituted or unsubstituted aryl in the compounds of Formula (I). Thus, R_6bmay be hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C₁-C₆alkoxy, C_1-6haloalkoxy, C_1-6-alkoxy-C_1-6-alkyl-, aryl-C_1-6alkyl-, C_2-9heteroalicyclyl-C_1-4alkyl-, C_1-6-alkoxy-aryl-, haloaryl, and aryl. Particular examples of compounds of Formula (I) have an R_6bgroup selected from hydrogen, —(CH₂)C(CH₃)₃, —(CH₂)CONH₂, phenyl, phenyl substituted with 1 to 3 halogens, —CH(CH₃)OC(CH₃)₃, —CH₂-phenyl-OCH₃,-phenyl-OCH₃, —CH₂-pyridyl, CH₂-cyclohexyl-CH₂CO₂H, —CH₂-cyclohexyl-CH₂CONH₂, CH₂-cyclohexyl-CH₂-tetrazolyl, —CH₂-cyclohexyl-CH₂OH, —CH₂-cyclohexyl-NHSO₂CH₃, —CH₂-cyclohexyl-NHSO₂CH₂CF₃, —CH₂-cyclohexyl-CH₂CN, —CH₂-phenyl-CH₂CO₂H, —CH₂-phenyl-CH₂CONH₂, —CH₂-phenyl-CH₂CONH₂CH₃, —CH₂-phenyl-CH₂-tetrazolyl, —CH₂-phenyl-CONH₂, —CH₂-phenyl-SO₂NH-cyclopropyl, —CH₂-phenyl-SO₂CH₃, —CH₂-phenyl-NHSO₂CF₃, —CH₂-phenyl-NHSO₂CH₃, —CH₂-phenyl-NHSO₂CHF₂, —CH₂-pyridyl-CH₃, —CH₂-pyridyl-SO₂CH₃, —CH₂-pyridyl-CH₂CONH₂, —CH₂-pyrimidyl-NHSO₂CH₃, —CH₂-piperidyl-COCH₃, —CH₂-piperidyl-SO₂CH₃, —CH₂-piperidyl-SO₂CF₃, —CH₂-thienyl-CH₂CO₂H, —CH₂-cyclobutyl-CH₂CO₂H, —CH₂-cyclobutyl-CH₂CONH₂, —CH₂-cyclobutyl-CO₂H, —CH₂-cyclobutyl-CONH₂, —CH₂-tetrahydrothiopyryl, —CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂-tetrahydrofuranyl, —CH₂-tetrahydropyranyl, —CH₂-oxetanyl, and —CH₂-pyranyl.
Some embodiments relate to R_6aand R_6bbeing taken together to form a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, substituted or unsubstituted C_2-9heteroalicyclyl.
Ring system B in compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein is not intended to be particularly limited, unless otherwise indicated. In some embodiments, ring system B is a mono- or bicyclic aryl, a mono- or bicyclic heteroaryl, or a bicyclic heteroalicyclyl. Further, ring system B may be a monocyclic heteroalicyclyl. Ring system B may, but need not, be substituted with at least one of R_4aor R_4bthat is a non-hydrogen substituent. Compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, may also have a ring system B that is a mono-cyclic, 6-membered aryl or heteroaryl substituted with R_4a. In some embodiments ring system B is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, naphthyl and furanyl, such as from the group consisting of phenyl, pyridyl, and pyrimidinyl. Some embodiments ring system B is selected from the group consisting of phenyl, and pyridyl. In some embodiments, n is an integer selected from 1, 2, 3 and 4. Alternatively, n may be 0 meaning that R_4awill be the only substituent on ring system B.
In some embodiments, the ring B is a bicyclic ring system, such as bicyclic aryl, bicyclic heteroaryl, or bicyclic heteroalicyclyl ring systems, e.g. benzazepine, benzazocines, benzimidazole, benzimidazoline, benzodioxin, benzodioxole, benzofuran, benzoisothiazole, benzothiadiazine, benzothiadiazole, benzothiazepine, benzothiazine, benzothiazole, benzothiophene, benzotriazole, benzoxadiazole, benzoxathiole, benzoxazepine, benzoxazine, benzoxazole, benzisoxazole, benzodioxole, chromane, chromene, coumarin, cyclopentapyridine, cyclopentapyrimidine, diazanaphthalene, dioxolopyridine, dioxolopyrimidine, dihydrobenzodioxine, dihydrobenzooxathiine, furofuran, furopyridine, furopyridine, furopyrimidine, imidazopyridine, imidazopyrimidines, indane, indazole, indene, indole, indoline, indolizines, isobenzofuran, isochromenes, isoindole, isoindoline, isoquinoline, naphthalene, naphthyridine, oxathiolopyridine, oxathiolopyrimidine, oxazolopyridine, oxazolopyrimidine, pteridine, purine, pyranopyridine, pyranopyrimidine, pyrazolodiazepines, pyrazolopyridine, pyrazolopyrimidine, pyridobenzthiazine, pyridodiazepene, pyridooxazine, pyridopyrazine, pyridopyrimidine, pyridothiazine, pyrimidooxazine, pyrimidopyrimidine, pyrimidothiazine, pyrrolizine, pyrroloimidazole, pyrrolopyrazine, pyrrolopyridine, pyrrolopyrimidine, quinazoline, quinoline, quinolone, quinolizidine, quinoxaline, tetralin, thiazolopyridine, thiazolopyrimidine, thienodiazepine, thienopyridine, thienopyrimidine, thiochromane, thiochromene, thiopyranopyridine, thiopyranopyrimidine, triazolopyridazine, triazolopyridine or triazolopyrimidine, all of which may be unsubstituted or substituted.
Like ring system B, the ring system C in compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, is not intended to be particularly limited in scope, unless otherwise specified. According to one embodiment, ring system C is a C_2-9heteroalicyclyl In some embodiments ring system C is a 4-7-membered heteroalicyclyl. For example, ring system C may be pyrrolidinyl or morpholinyl.
The integer values of n and m may take any particular combination. In one embodiment, m is 1 or 2. Further, m may be 0 (zero) meaning that the ring system C is unsubstituted. In another embodiment, n is an integer selected from 1, 2, 3 and 4. Alternatively, n may be 0 meaning that R_4awill be the only substituent on ring system B. Alternatively, n may be 0 and R_4ahydrogen, i.e. the ring system B is unsubstituted.
According to yet another embodiment, the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, have R₅being —(CR₈R₉)p-C(═O)NR₈R₉; R₈and R₉are independently of each other selected from H and substituted or unsubstituted C_1-6alkyl; p is 0; and R_6bis hydrogen or —(CH₂)C(CH₃)₃.
Compounds disclosed herein may also comprise compounds of Formula (IIb):
wherein:
C is a pyrrolidine ring or a morpholine ring;
R1 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-4alkyl, and substituted or unsubstituted C_1-4alkoxy; some compounds of Formula (IIb) have an R1 that is hydrogen or —CF₃;
R₃is independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-4alkyl, and halogen;
R_4ais selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl-C_1-6alkyl; some compounds of Formula (IIb) have an R_4athat is selected from the group consisting of halogen, —CF₃, —OCF₃, iso-propyl, tert-butyl, —C_1-6alkoxy, C_1-6alkoxy substituted with one or more halogens, and phenyl;
R_4bis independently selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, —C(═O)R₁₀;
R₅is selected from the group consisting of substituted or unsubstituted C_3-7cycloalkyl, substituted or unsubstituted C_3-7cycloalkenyl, substituted or unsubstituted C_2-6heteroalicyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R_6aare R_6bare independently selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6alkyl; and
m is an integer independently selected from the group consisting of 1, 2, and 3; and
n is an integer independently selected from the group consisting of 1, 2, 3, and 4.
In compounds of Formula (IIb), R₅may be selected from the group consisting of substituted or unsubstituted C_4-7cycloalkyl, substituted or unsubstituted C_6-12membered aryl, substituted or unsubstituted 4-membered heteroalicyclyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 5-membered heteroalicyclyl, substituted or unsubstituted 6-membered heteroaryl, a substituted or unsubstituted 6-membered heteroalicyclyl, substituted or unsubstituted 7-membered heteroaryl, and a substituted or unsubstituted 7-membered heteroalicyclyl. Thus, R₅may be selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, thietanyl, pyrrolyl, pyrazoleyl imidazolyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathianyl thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolanyl, dioxanyl, furyl, dihydrofuranyl, furazanyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dithianyl, thiopyranyl, thianyl, thienyl, oxetanyl, quinolyl, isoquinolyl, indolyl, iso-indolyl, and tetrahydrothienyl, any of which may be substituted or unsubstituted. Especially, R₅may be selected from the group consisting of cycloheptyl, cyclohexyl, cyclopentyl, dioxanyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxathianyl, phenyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, tetrazolyl, thianyl, thiazolyl, thienyl, thiomorpholinyl, thiopyryl, and triazolyl, any of which may be substituted or unsubstituted.
If substituted, R₅may be substituted with —(CH₂)q(R_5a), wherein R_5ais independently selected from the group consisting of —CH₂COOR₂₀, —CH₂CONR₂₁R₂₂, oxo, —CN, —CH₂—CN, C_1-6alkyl, —CH₂-imidazolyl, —CH₂—SO₂R₂₀, —CH₂C(CH₃)₂(OR₂₀), —OR₂₀, —CH₂-triazolyl, —CF₃, dimethyl substituted-imidazolyl-2,4-dione, —CH₂—SO₂NR₂₁R₂₂, morpholinyl, —C(═O)-morpholinyl, piperidyl-CH₂OR₂₀, —OCH₂-tetrahydrofuryl, piperazinonyl, piperidinyl-CONR₂₁R₂₂, —OH, —CONR₂₁R₂₂, —CH(OR₂₀)CH₃, —COOR₂₀, —CH₂-pyrrolidyl, C_1-6alkylene-OH, cyclopentyl, pyrrolidonyl, —NR₂₁SO₂R₂₀, tetrazolyl, —CH₂-tetrazolyl, —CH₂OR₂₀, acyl, —SOR₂₀, —SO₃R₂₀, —SO₂R₂₀, —SO₂NR₂₁R₂₂, and halogen;
R₂₀, R₂₁, and R₂₂are independently of each other selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, —CN, substituted or unsubstituted C_3-6cycloalkyl, substituted or unsubstituted C_2-6heteroalicyclyl; and
q is an integer selected from 0, 1 or 2.
Further, R₅may be selected from the group consisting of unsubstituted aryl, unsubstituted heteroaryl, aryl substituted with one or more C_1-6alkoxy, aryl substituted with —CH₂COOC_1-6alkyl, aryl substituted with —CH₂CONH—(C_1-6alkyl), aryl substituted with CH₂CON(C_1-6alkyl)₂, —(CH₂)—C(═O)OR₇, —C(═O)OR₇, —(CH₂)—C(═O)NR₈R₉or —C(═O)NR₈R₉, heteroaryl substituted with —(CH₂)—C(═O)NR₈R₉or SO₂R₇, and C_2-9heteroalicyclyl substituted with —(CH₂)—C(═O)NR₈R₉or SO₂R₇;
R₇, R₈, and R₉are independently selected from the group consisting of hydrogen, unsubstituted C_1-6alkyl, and C_1-6alkylene substituted with furanyl.
Compounds disclosed herein may also comprise compounds of Formula (IIc):
wherein:
R₃is hydrogen, fluorine or methyl;
R_4ais selected from the group consisting of hydrogen, fluorine, chlorine, —C(CH₃)₃, —CH₂(CH₃)₂, —CF₃, —OCH₃, —OC(CH₃)₃, and —OCF₃;
R_4bis selected from the group consisting of hydrogen, fluorine, chlorine, and —OCH₃;
m and n are integers independently selected from 1 or 2;
Y is OR₇or NR₈R₉;
R₇, R₈, and R₉are independently selected from H and C_1-6alkyl; and
B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, quinolinyl, and 1,4-benzodioxanyl; and
C is pyrrolidinyl or morpholinyl.
Compounds disclosed herein may also comprise compounds of Formula (IId):
wherein:
B is selected from phenyl, pyridyl and pyrimidyl;
C is pyrrolidinyl or morpholinyl;
R_4ais a substituent arrange in para- or meta-position compared to the carbon atom in the ring system C, and selected from the group consisting of hydrogen, halogen, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl (for example —CF₃), C_1-4haloalkoxy (for example —OCF₃), and heteroaryl;
R₅is a ring selected from the group consisting of phenyl, pyrimidinyl, pyridyl, pyridinyl-N-oxide, cyclohexyl, pyrrolyl, pyrazolyl, furanyl, pyrrolidonyl, tetrahydrofuranyl, tetrahydropyranyl, benzopyrrolidonyl, cyclobutyl, oxetanyl, tetrahydrothiophenyl, tetrahydro-2H-thiopyranyl, cyclopentyl, cycloheptanyl, tetrahydrothiophenyl-1,1-dioxide, tetrahydro-2H-thiopyranyl-1,1-dioxide, 1,4-oxathianyl-4,4-dioxide, and piperidinyl, any of which may be unsubstituted or substituted with (R_5b)t;
R_5b, when present, is independently selected from the group consisting of —CH₂COOR₂₀, —CH₂CONR₂₁R₂₂, oxo, —CN, —CH₂—CN, —C_1-6alkyl, —CH₂-imidazolyl, —CH₂—SO₂R₂₀, —CH₂C(CH₃)₂(OR₂₀), —OR₂₀, —CH₂-triazolyl, —CF₃, dimethyl substituted-imidazolidinyl-2,4-dione, —CH₂—SO₂NR₂₁R₂₂, morpholinyl, —C(═O)-morpholinyl, piperazinonyl, piperidinyl-CONR₂₁R₂₂, —OH, —COR₂₀, —CONR₂₁R₂₂, —CH(OR₂₀)CH₃, —COOR₂₀, —CH₂-pyrrolidonyl, —C_1-6-alkylene-OH, -cyclopentyl, -pyrrolidonyl, -tetrazolyl, —CH₂-triazolyl, —CH₂OR₂₀, -acyl, —SOR₂₀, —SO₂R₂₀, —SO₂NR₂₁R₂₂, —NR₂₁SO₂R₂₀, and halogen;
R₂₀, R₂₁, and R₂₂are independently selected from H, —C_1-6alkyl, —C_1-6haloalkyl, —C_3-6cycloalkyl, and —C_1-6heteroalicyclyl; and
t is an integer selected from 1 or 2.
Compounds disclosed herein may also comprise compounds of Formula (IIe):

- or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and stereoisomers thereof, wherein:

n, p and v are an integer selected from 0, 1 and 2;
R is hydrogen or C_1-4alkyl;
R₁is selected from the group consisting of hydrogen, —OH, halogen, substituted or unsubstituted C_1-4alkyl, and substituted or unsubstituted C_1-4alkoxy;
R₂is selected from the group consisting of hydrogen, halogen, C_1-4alkyl, C_1-4haloalkyl, and C_1-4hydroxyalkyl;
or R and R₂are combined to form a fused ring;
R₃is selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, oxo, and —C(═O)R₁₀;
R_4ais selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C_1-6alkyl;
R_4bis selected from the group consisting of hydrogen, oxo, halogen, —OH, substituted or unsubstituted C_1-4alkyl, and substituted or unsubstituted C_1-4alkoxy, —C(═O)R₁₀;
R_5ais selected from the group consisting of hydrogen, halogen, oxo, —CN, —OH, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted C₂-C₈heteroalicyclyl, substituted or unsubstituted C₂-C₈heteroalicyclyl-C_1-6alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl-C_1-6alkyl, —(CH₂)_qCO₂R₂₀, —(CH₂)_q—CONR₂₀R₂₁, —(CH₂)_q—SOR₂₀, —(CH₂)_q—SO₂R₂₀, —(CH₂)_q—SO₂NR₂₁R₂₂, and —(CH₂)_qNR₂₁SO₂R₂₀;
q is an integer selected from 0 or 1;
R₂₀, R₂₁, and R₂₂are independently of each other selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, —CN, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-6heteroalicyclyl, or R₂₁and R₂₂are combined to form a C_3-6cycloalkyl;
R_6a, R_6bare independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_2-6alkynyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_1-6heteroalkyl, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R_6aand R_6bare taken together to form and oxo group or a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl, or R_6aand R₁₃are taken together to form a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-5heteroalicyclyl;
R₇, R₈, and R₉are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl;
R₁₀is selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, —OH, —NH₂, —NH(C_1-6alkyl), —N(C_1-6alkyl)₂, and C_3-7cycloalkyl;
R₁₃, if not to be taken together with R_6a, is absent, or selected from the group consisting of hydrogen, —CN, —OH, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, and —(CR₈R₉)p-C(═O)OR₇, —(CR₈R₉)p-SO₂R₇and —(CR₈R₉)p-C(═O)NR₈R₉;
B is a ring system selected from the group consisting of aryl, heteroaryl, and, C₂-C₉bicyclic heteroalicyclyl;
D is a ring system selected from the group consisting of aryl, heteroaryl, C_3-8cycloalkyl and, C₂-C₉heteroalicyclyl,
C is a ring system selected from C_2-9heteroalicyclyl, and
with the proviso the compound is not:
Some embodiments relates to the compound according to Formula (IIe) wherein
R₃is selected from the group consisting of hydrogen, halogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, oxo, C_1-4alkoxy and C_1-4haloalkoxy;
R_4ais selected from the group consisting of hydrogen, halogen, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, and heteroaryl;
R_4bis selected from the group consisting of hydrogen, oxo, halogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, and C_1-4haloalkoxy;
R_6ais selected from the group consisting of hydrogen, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, and C_1-6haloalkoxy;
R_6bis selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6alkoxy-C_1-6alkyl, C_1-6haloalkoxy, aryl-C_1-6alkyl, substituted or unsubstituted C_2-9heteroalicyclyl-C_1-6alkyl, and substituted or unsubstituted aryl;
or R_6aand R_6bare taken together to form and oxo group or a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl,
or R_6aand R₁₃are taken together to form a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-5heteroalicyclyl;
In some embodiments the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, B is aryl or heteroaryl, for example phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, naphthyl and furanyl, unless otherwise specified. Some embodiments relates to B being phenyl, pyrimidyl or pyridyl.
In some embodiments the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, B is a 6-membered aryl substituted with R_4ain the para-position or meta-position, a 6-membered heteroaryl substituted with R_4ain the para-position or meta-position, or a 5-membered heteroaryl substituted with R_4ain 2- or 3-position, unless otherwise specified. In some embodiments the 6-membered aryl is phenyl and the 6-membered heteroaryl is pyridyl or pyrimidinyl. Some embodiments relate to R_4abeing selected from the group consisting of halogen, —CN, C_1-4alkyl, C_1-4haloalkyl, C₁-C₄alkoxy, C_1-4haloalkoxy and heteroaryl, for example isopropyl, —CN, ethoxy, CF₃, and —OCF₃. Some embodiments relate to R_4bbeing selected from the group consisting of hydrogen, oxo, halogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C₁-C₄alkoxy, C_1-4haloalkoxy, and heteroaryl. Some embodiments relate to R_4abeing selected from the group consisting of halogen, —CN, C_1-4alkyl, C_1-4haloalkyl, C₁-C₄alkoxy, and C_1-4haloalkoxy, for example isopropyl, ethoxy, —CF₃, —CHF₂, —OCF₃, and —OCHF₂and R_4bbeing selected from the group consisting of hydrogen, halogen, and —OH.
In some embodiments the compounds of Formulae (IIe), D is selected from the group consisting of aryl, such as phenyl; heteroaryl, such as pyridyl, and pyrimidyl; C_3-8cycloalkyl, such as cyclohexyl; and C_2-8heteroalicyclyl, such as piperidyl, tetrahydro-2H-pyranyl, thiopyranyl, tetrahydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl-1,1-dioxide, pyrrolidinyl, thianyl and oxetanyl, all which may be substituted with one or more R_5a. Some embodiments relates to R_5abeing selected from hydrogen, C_1-6alkyl, such as methyl and ethyl; C_1-6hydroxyalkyl, such as methanol and ethanol; —(CH₂)_q—CN; —(CH₂)_q—CO₂R₂₀; —(CH₂)_q—C_1-6alkoxy, such as methoxy and ethoxy and methoxyethyl; oxo, —(CH₂)_q-heteroaryl, such as —(CH₂—)_q-tetrazolyl, —(CH₂—)_q-imidazolyl, —(CH₂—)_q-triazolyl; —(CH₂—)_q—CONR₂₀R₂₁; —(CH₂—)_q—COR₂₀; —(CH₂—)_q—SO₂R₂₀; —(CH₂—)_q—NR₂₁SOR₂₀; and —(CH₂—)_q—SO₂NR₂₁R₂₂;
R₂₀, R₂₁, and R₂₂are independently of each other selected from the group consisting of hydrogen, —OH, substituted or unsubstituted C_1-6alkyl, —CN, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-6heteroalicyclyl, or R₂₁and R₂₂are combined to form a C_3-6cycloalkyl; and
q is an integer selected from 0 or 1.
As for any given group disclosed herein, the ring system D may comprise further hydrogen(s) than the one(s) provided by R_5abeing hydrogen.
In some embodiments R₂₀, R₂₁, and R₂₂are independently of each other selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, —CF₃, and —CHF₂,
In some embodiments the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, R₁₃is absent, or selected from the group consisting of hydrogen, —OH, —CN, C_1-4hydroxyalkyl, C_1-6haloalkyl, —(CH₂—)_qCO₂H, —(CH₂—)_q—SO₂R₂₀, —(CH₂—)_q—NR₂₁SO₂R₂₀and C_1-6alkoxy, or R₁₃combined with the atom to which it is attached and an adjacent R_5ato form a C_3-5cycloalkyl, or C_2-4heteroalicyclyl.
In some embodiments the compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, R_6ais hydrogen, or combined with R_5a, R_6bor R₁₃to form ring system such as a C_3-6cycloalkyl or C_2-5-heteroalicyclyl; R_6bis hydrogen or absent. In some embodiments both R_6aand R_6bare hydrogen.
In some embodiments the compounds according to Formula (IIe)
R is hydrogen; R₂is selected from Cl or F; or R and R₂are combined to form a pyrrolo[2,3-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
m is an integer selected from 0, 1 and 2;
n is an integer selected from 0 and 1;
v is an integer selected from 0 and 1;
R₃is hydrogen or fluoro
B is aryl or heteroaryl, for example phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, naphthyl or furanyl;
C is C_2-9heteroalicyclyl, for example pyrrolidinyl or morpholinyl;
R_4ais selected from the group consisting of halogen, C_1-4alkyl, C_1-4haloalkyl, C₁-C₄alkoxy, C_1-4haloalkoxy and heteroaryl, for example —CF₃, —CHF₂, —OCF₃, —OCHF₂, and triazolyl;
R_4bis selected from the group consisting of hydrogen, —OH, oxo, halogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C₁-C₄alkoxy, C_1-4haloalkoxy, and heteroaryl.
D is selected from the group consisting of aryl, such as phenyl; heteroaryl, such as pyridyl, and pyrimidyl; C_3-8cycloalkyl, such as cyclopentyl and cyclohexyl; and C_2-8heteroalicyclyl, such as a mono-cyclic or a bridged C_2-8heteroalicyclyl, such as piperidyl, tetrahydro-2H-pyranyl, thiopyranyl, tetrahydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl-1,1-dioxide, oxetanyl, tropanyl, and pyrrolidinyl, all which may be substituted with one or more R_5a;
R_5ais selected from halogen, C_1-6alkyl, such as methyl and ethyl; C_1-6hydroxyalkyl, such as methanol and ethanol; C_1-6haloalkyl, such as —CF₃, —(CH₂)_q—CN; —(CH₂)_q-acyl; —(CH₂)_q—C_1-6alkoxy, such as methoxy and ethoxy and methoxyethyl; —(CH₂)_q-heteroaryl, such as —(CH₂—)_q-tetrazolyl, —(CH₂—)_q-imidazolyl, —(CH₂—)_q-triazolyl; —(CH₂—)_q—CONR₂₀R₂₁; —(CH₂—)_q—COR₂₀; —(CH₂—)_q—SO₂R₂₀; —(CH₂—)_q—NR₂₁SOR₂₀; —(CH₂—)_q—SO₂NR₂₁R₂₂;
R₂₀, R₂₁, and R₂₂are independently of each other selected from the group consisting of hydrogen, —OH, substituted or unsubstituted C_1-6alkyl, —CN, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-6heteroalicyclyl, or R₂₁and R₂₂are combined to form a C_3-6cycloalkyl; and
q is an integer selected from 0 or 1;
R₁₃is absent, or selected from the group consisting of hydrogen, —OH, —CN, C_1-4hydroxyalkyl, C_1-6haloalkyl, —(CH₂—)_q—SO₂R₂₀, —(CH₂—)_q—NR₂₁SO₂R₂₀and C_1-6alkoxy, or R₁₃combined with the atom to which it is attached and an adjacent R_5ato form a C_3-5cycloalkyl, or C_2-4heteroalicyclyl; In some embodiments R₁₃is absent or hydrogen.
R_6ais hydrogen, or combined with R_5a, R_6bor R₁₃to form ring system such as a C_3-6cycloalkyl or C_2-5-heteroalicyclyl; R_6bis hydrogen or absent; for example both R_6aand R_6bare hydrogen.
In such an embodiment, B may be phenyl or pyridyl. Further, B may be phenyl with R_4ain the para-position or meta-position, or a 6-membered heteroaryl substituted with R_4ain the para-position or meta-position, or a 5-membered heteroaryl substituted with R_4ain 2- or 3-position, wherein R_4ais selected from a group other than hydrogen.
According to one aspect disclosed herein are compounds of Formula (X)
or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and stereoisomers thereof, wherein:
Y₁is NR or O;
Y₂is N or C;
R is hydrogen or substituted or unsubstituted C_1-4alkyl;
R₁is selected from the group consisting of hydrogen, —OH, halogen, —CN, —NO₂, —NH₂, alkylamino, amide, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, carbonyl, thisocarbonyl, C amido, N amido, S-sulfonamido, N sulfonamide, silyl, sulfenyl, sulfinyl, sulfonyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_2-6alkynyl, substituted or unsubstituted C_1-6heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C_3-9cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroaliyclyl;
R₂is selected from the group consisting of hydrogen, —OH, halogen, —CN, —NO₂, —NH₂, alkylamino, amide, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, carbonyl, thisocarbonyl, C amido, N amido, S-sulfonamido, N sulfonamide, silyl, sulfenyl, sulfinyl, sulfonyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_2-6alkynyl, substituted or unsubstituted C_1-6heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C_3-9cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroaliyclyl;
or R and R₂are combined to form a fused ring;
R_4ais selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl-C_1-6alkyl;
R₃and R_4bare independently selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, —C(═O)R₁₀;
R₅is selected from the group consisting of —(CR₈R₉)pOR₁₂, —(CR₈R₉)p-CR₁₃R₁₄R₁₅, —(CR₈R₉)p-C(═O)OR₇, and —(CR₈R₉)p-C(═O)NR₈R₉;
n, m, and p are integers independently selected from the group consisting of 0, 1, 2, 3 and 4;
R_6a, R_6bare independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_1-6alkynyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_1-6heteroalkyl, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R₇, R₈, R₉, and R₁₂, are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl;
R₁₀is selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, —NH₂, —NH(C_1-6alkyl), —N(C_1-6alkyl)₂, and C_3-7cycloalkyl;
R₁₃is absent, or selected from the group consisting of hydrogen, —OH, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, and —(CR₈R₉)p-C(═O)OR₇, and —(CR₈R₉)p-C(═O)NR₈R₉;
R₁₄and R₁₅are independently selected from the group consisting of hydrogen, and substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_3-6cycloalkyl, substituted or unsubstituted C_2-9heteroalicyclyl; or
R₁₄and R₁₅are combined to form a ring system selected from the group consisting of substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl substituted or unsubstituted C_2-9heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
A, B and C are independently of each other a ring system selected from the group consisting of aryl, heteroaryl, C_3-8cycloalkyl, C_3-8cycloalkenyl, and C_2-9heteroaliyclyl.
In a related embodiment A is selected from the group consisting of phenyl, pyridyl, pyrrolyl, furyl, pyranyl, thiopyranyl, thienyl, pyrazinyl, pyrimidinyl, triazinyl, naphthyl, indolyl, iso-indolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, and oxazolyl. In yet a related embodiment A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, and wherein R₁is arranged in position 1 of the 6 membered ring, R₁is arranged in position 4 of the 6 membered ring, Y₁arranged in position 3 of the 6 membered ring, Y₂arranged in position 5 of the 6 membered ring. In a related embodiment R₁is selected from the group consisting of hydrogen, —OH, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, and substituted or unsubstituted C_2-4alkenyl; and R₂is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, —CN, —OH and —NO₂; or R and R₂are combined to form a fused ring;
In yet a related embodiment B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic heteroalicyclyl; C is a ring system selected from the group consisting of C_2-9heteroalicyclyl and heteroaryl; wherein B is attached to a carbon atom adjacent the N atom of ring system C.
In some embodiments whenever a halogen is specified as a substituent the halogen is selected from fluoro or chloro.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the TAMRA-labelled probe.

FIG. 2 illustrates the characterisation of the Fluorescence Polarization (FP) assay with the TAMRA-labelled probe used in the FP assay.

FIG. 3 depicts the assay results of example no. 89 in (A) Fluorescence Polarization Assay, (B) RORγ Reporter Assay (Gal4), and (C) Th17 Assay. Specific examples of compounds are disclosed in Table 1 below.

TABLE 1

Example Compounds by Structure and Name.

Ex.
No.	Structure	Name

4		3-[[2-[4-[2-(4- phenylphenyl)pyrrolidin-1- yl]pyrrolo[2,3-d]pyrimidin-7- yl]butanoylamino]methyl]furan-2- carboxamide

5		(2R)-2-[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide or (2R)-2- [[5-fluoro-6-[(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

6		(2R)-4,4-dimethyl-2-[[6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]pentanamide

9		(2R)-2-[[6-[2-(1,3-benzothiazo1-2- yl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4-yl]amino]-3-(2,4,5- trifluorophenyl)propanamide

11		(2R)-2-[[6-[2-(2,4- dichlorophenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

13		(2R)-2-[[5-fluoro-2- (trifluoromethyl)-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

14		(2R)-4,4-dimethyl-2-[[5-methyl-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]pentanamide

15		(2R)-2-[[2,5-dimethyl-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

16		5-fluoro-N-(3-methoxy-1,3- dimethyl-butyl)-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

17		(2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3-(4- methoxyphenyl)propanamide

18		(2R)-2-[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

19		(2R)-2-[[6-[2-(4-tert- butylphenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

20		(2R)-2-[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

21		N-(3,3-dimethylbutyl)-5-fluoro-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

23		(2R)-2-[[5-fluoro-6-[2-(6- quinolyl)pyrrolidin-1-yl]pyrimidin- 4-yl]amino]-4,4-dimethyl- pentanamide

24		(2R)-2-[[6-[2-(2,3-dihydro-1,4- benzodioxin-6-yl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

29		(2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3-(4- methoxyphenyl)propan-1-ol

30		(2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentan-1-ol

31		(2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]-methyl- amino]-N,4,4-trimethyl- pentanamide

32		2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid

33		(2R)-2-[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4- methyl-pentanoic acid

34		(2R)-2-[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4- methyl-pentanamide

35		(2R)-2-[[6-[2-[2-chloro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-pyrimidin-4- yl]amino]-4,4-dimethyl- pentanamide

36		(2R)-2-[[6-[2-[2-chloro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-pyrimidin-4- yl]amino]-4,4-dimethyl-pentanoic acid

37		(2R)-2-[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3-(4- fluorophenyl)propanamide

38		(2R)-2-[[5-fluoro-6-[3-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

39		(2R)-2-[[3-fluoro-2-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-4-pyridyl]amino]-4,4- dimethyl-pentanamide

40		2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

41		5-fluoro-N-(1-methyl-2- tetrahydropyran-4-yl-ethyl)-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

42		(2R)-2-[[5-fluoro-6-[2-[5- (trifluoromethyl)-2- pyridyl]pyrrolidin-1-yl]pyrimidin-4- yl]amino]-4,4-dimethyl- pentanamide

43		(2R)-2-[[6-[2-(4-tert- butoxyphenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

44		4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzoic acid

45		3-[[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methyl]- 5,5-dimethyl-imidazolidine-2,4- dione

46		[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methane- sulfonamide

48		5-fluoro-N-[[4- (trifluoromethyl)phenyl]methyl]-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

51		(2R)-3-tert-butoxy-2-[[5-fluoro-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]butanamide

52		(2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3- tetrahydropyran-4-yl-propanamide

53		N-[(3,4-dimethoxyphenyl)methyl]- 5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

54		N-[(2,3-dimethoxyphenyl)methyl]- 5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

55		N-[1-(3,4-dihydro-2H-1,5- benzodioxepin-7-yl)propyl]-5- fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

56		5-fluoro-N-[(4- morpholinophenyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

57		[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]- morpholino-methanone

58		[1-[5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 2-pyridyl]-4-piperidyl]methanol

59		5-fluoro-N-[[4-(tetrahydrofuran-2- ylmethoxy)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

60		4-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]piperazin- 2-one

61		1-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]piperidine- 3-carboxamide

62		(2R)-2-[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide or (2R)-2- [[5-fluoro-6-[(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

63		(2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3-(2- oxopyrrolidin-3-yl)propanamide

64		N-[(1R)-3,3-dimethyl-1-morpholin- 2-yl-butyl]-5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

65		(2R)-2-[[5-fluoro-6-[2-[2-methoxy-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

66		3-fluoro-N-[(6-methyl-3- pyridyl)methyl]-4-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyridin-2-amine

67		1-[(3,4-dimethoxyphenyl)methyl]-4- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-b]pyridine

68		(2R)-2-[[5-fluoro-6-[3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

69		7-[(3,4-dimethoxyphenyl)methyl]-4- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-d]pyrimidine

70		methyl 2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetate

71		1-[2-[(1R)-1-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3,3- dimethyl-butyl]morpholin-4- yl]ethanone

72		(2R)-2-[[5-fluoro-6-[2-[3-fluoro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide

73		5-fluoro-4-[2-[3-fluoro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-6-[(6-methyl-3- pyridyl)methoxy]pyrimidine

74		5-fluoro-4-[(6-methyl-3- pyridyl)methoxy]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidine

77		(2R)-2-[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide or (2R)-2-[5-fluoro-6- [(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide

78		(2R)-2-[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide or (2R)-2-[5-fluoro-6- [(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide

79		2-[4-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]oxymethyl]phenyl]acetic acid

80		(2R)-2-[5-fluoro-6-[5-[4- (trifluoromethyl)phenyl]pyrazol-1- yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide

81		2-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid

83		2-[4-[[5-fluoro-6-[[4- (trifluoromethyl)phenyl]methylamino] pyrimidin-4- yl]oxymethyl]phenyl]acetic acid

84		2-[4-[[5-fluoro-6-[2-[6- (trifluoromethyl)-3- pyridyl]pyrrolidin-1-yl]pyrimidin-4- yl]oxymethyl]phenyl]acetamide

85		2-[4-[[4-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-d]pyrimidin-7- yl]methyl]phenyl]acetic acid

86		2-[5-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]oxymethyl]pyrimidin-2- yl]acetamide

87		2-[5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]pyrimidin-2- yl]acetamide

88		4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzonitrile

89		5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

90		5-fluoro-6-[2-(4- methoxyphenyl)pyrrolidin-1-yl]-N- [(6-methyl-3- pyridyl)methyl]pyrimidin-4-amine

91		2-[4-[[[5-fluoro-6-[3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid

93		5-fluoro-N-[(4- methylcyclohexyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

94		5-fluoro-N-[[4-(imidazol-1- ylmethyl)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

95		5-fluoro-N-[[4- (methylsulfonylmethyl)phenyl] methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

96		5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[5-[4- (trifluoromethyl)phenyl]triazol-1- yl]pyrimidin-4-amine

97		5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[2-[4- (trifluoromethoxy)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

98		1-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]-2-methyl- propan-2-ol

99		5-fluoro-N-[(2-methoxy-6-methyl- 3-pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

100		5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]pyridin-2-ol

104		2-[1-[5-fluoro-6-[(6-methyl-3- pyridyl)methylamino]pyrimidin-4- yl]pyrrolidin-2-yl]-5- (trifluoromethyl)pheno1

105		5-fluoro-N-[(1-methylpyrrol-3- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

106		5-fluoro-N-[(1-methylpyrazo1-4- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

107		5-fluoro-N-[(5-methyl-2- furyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

108		5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]pyrrolidin-2-one

109		4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 1-methyl-pyrrolidin-2-one

110		5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- N,N-dimethyl-tetrahydrofuran-2- carboxamide

111		5-fluoro-N-[(4- methoxytetrahydropyran-4- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

112		1-[6-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 2-methyl-3-pyridyl]ethanol

113		5-fluoro-N-[(2-methoxy-4- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

114		5-fluoro-N-[(6-methoxy-3- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

115		5-fluoro-N-[[4-(1,2,4-triazol-1- ylmethyl)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

116		5-fluoro-N-[(6-methoxy-3- pyridyl)methyl]-N-methyl-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

117		2-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid

118		2-[4-[[[5-fluoro-6-[(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid

119		2-[4-[[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid

120		4-[2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]ethyl]benzoic acid

121		[3-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]pyrrolidin-1-yl]-(4- pyridyl)methanone

122		5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]indolin-2-one

123		5-fluoro-N-[3-methyl-1-(1H- tetrazol-5-yl)butyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

124		1-[[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methyl] pyrrolidin-2-one

126		5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-N-[[6-(trifluoromethyl)-3- pyridyl]methyl]pyrimidin-4-amine

128		2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]ethanol

129		4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran- 4-ol

130		1-cyclopentyl-4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]pyrrolidin-2-one

131		5-fluoro-N-[(4-methoxy-2- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

132		5-fluoro-N-[(6-methyl-2- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

134		9-[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]-3,9- diazaspiro[4.5]decan-2-one

135		4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]-methyl- amino]methyl]-1-methyl-pyrrolidin- 2-one

136		N-[(5-ethyl-2-pyridyl)methyl]-5- fluoro-N-methyl-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

137		1-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]pyrrolidin- 2-one

138		5-fluoro-N-[[4-(1H-tetrazol-5- yl)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

139		N-benzyl-5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

140		5-fluoro-N-(4-pyridylmethyl)- 6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

141		5-fluoro-N-(3-pyridylmethyl)- 6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

142		N-[(3,5-dimethoxyphenyl)methyl]- 5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

143		1-[3-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]pyrrolidin- 2-one

144		3-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- N-methyl-benzamide

145		3-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- N,N-dimethyl-benzamide

146		5-fluoro-N-[[3-(1,2,4-triazol-1- ylmethyl)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

147		5-fluoro-N-[[3- (methoxymethyl)phenyl]methyl]-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

148		2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl]acetic acid

150		5-fluoro-6-[2-(5-methyl-2- furyl)pyrrolidin-1-yl]-N-[(6-methyl- 3-pyridyl)methyl]pyrimidin-4- amine

151		N-(cyclobutylmethyl)-5-fluoro- 6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

152		5-fluoro-N-[(1- methylcyclobutyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

154		5-fluoro-N-(tetrahydrofuran-3- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

155		5-fluoro-N-(tetrahydropyran-2- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

159		5-fluoro-N-(tetrahydrothiophen-2- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

161		5-fluoro-N-[(4- methyltetrahydropyran-4- yl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

164		5-fluoro-N-(tetrahydrothiopyran-4- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

165		3-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydrothiophen- 3-ol

166		N-[(4,4- dimethylcyclohexyl)methyl]-5- fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

167		1-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]cycloheptanol

168		5-fluoro-N-[(2- methoxycyclohexyl)methyl]-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

169		4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydrothiopyran- 4-o1

170		N-[(1,1-dioxothiolan-2-yl)methyl]- 5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

175		N-[(2-tert-butyltetrahydropyran-3- yl)methyl]-5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

178		5-fluoro-N-[(4- isopropylcyclohexyl)methyl]-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

181		5-fluoro-N-(tetrahydrofuran-2- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

182		4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzenesulfonamide

183		N-[(6-chloro-3-pyridyl)methyl]-5- fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

184		N-[(1,1-dioxothiolan-3-yl)methyl]- 5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

185		5-fluoro-N-(3-thienylmethyl)-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

186		5-fluoro-N-(tetrahydropyran-3- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

188		5-fluoro-N-[[1- (methoxymethyl)cyclobutyl]methyl]- 6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

189		2-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]-N-methyl- acetamide

190		5-fluoro-N-[[4-(1H-tetrazol-5- ylmethyl)cyclohexyl]methyl]-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

191		1-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 1-piperidyl]ethanone

192		2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethoxy)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid

193		5-fluoro-N-[(1-oxidopyridin-1-ium- 3-yl)methyl]-6-[(2R)-2[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

194		5-fluoro-N-[(1-oxidopyridin-1-ium- 4-yl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

195		2-[4-[[4-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-d]pyrimidin-7- yl]methyl]phenyl]acetic acid

196		2-[4-[[4-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-d]pyrimidin-7- yl]methyl]phenyl]acetamide

197		5-fluoro-N-[(1-methylsulfonyl-4- piperidyl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

198		5-fluoro-N-[(3-methyloxetan-3- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

199		5-fluoro-N-[(2- methyltetrahydrofuran-2- yl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

200		2-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]cyclohexanol

201		5-fluoro-N-[(2- methyltetrahydrothiophen-2- yl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

202		N-[(4,4-dioxo-1,4-oxathian-2- yl)methyl]-5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

203		5-fluoro-N-(2-thienylmethyl)-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

204		2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

205		2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl]acetic acid

206		2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] acetamide

207		2-[5-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 2-thienyl]acetic acid

208		5-fluoro-N-(tetrahydropyran-4- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

209		5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[2-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

210		5-fluoro-6-[(2R)-2-[2-fluoro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-N-[(6-methyl-3- pyridyl)methyl]pyrimidin-4-amine

211		5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

212		5-fluoro-6-[4-methoxy-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-N-[(6-methyl-3- pyridyl)methyl]pyrimidin-4-amine

213		5-fluoro-N-[(5-methyloxazol-2- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

214		5-(((5-fluoro-6-(2-(4- (trifluoromethyl)phenyl)pyrrolidin- 1-yl)pyrimidin-4-yl)amino)methyl)- 1,3,4-oxadiazol-2-ol

215		5-fluoro-N-[1-(5-methyl-1,2,4- oxadiazo1-3-yl)propyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

216		5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]isoxazol-3-ol

217		[3-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methanol

218		N-(cyclopentylmethyl)-5-fluoro-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

219		5-fluoro-N-[(4- methylsulfonylphenyl)methyl]-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

220		3-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydrofuran- 3-ol

221		2-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- yl]ethanol

222		N-[(1,1-dioxothian-4-yl)methyl]-5- fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine

223		4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 1,1-dioxo-thian-4-ol

224		N-cyclopropyl-4-[[[5-fluoro-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzenesulfonamide

225		[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] methanol

226		4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzamide

227		[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methanol

228		[3-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]oxetan-3- yl]methano1

229		2-[4-[[[5-fluoro-6-[2-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

230		2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

231		2-[4-[[[6-[4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide

232		2-[4-[[[5-fluoro-6-[(2R)-2-[2- fluoro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

233		1-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- 1-piperidyl]ethanone

234		4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- 1,1-dioxo-thian-4-ol

235		5-fluoro-N-[(3-methyloxetan-3- yl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

236		N-cyclopropyl-4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl] benzenesulfonamide

237		5-fluoro-N-[(1-methylsulfonyl-4- piperidyl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

238		3-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydrofuran- 3-ol

239		2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran- 4-yl]ethanol

240		5-fluoro-N-[[4- (methylsulfonylmethyl) tetrahydropyran-4-yl] methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl] pyrrolidin- 1-yl]pyrimidin-4-amine

241		2-[4-[[[5-fluoro-6-[(2R,4R)-4- fluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide AND 2-[4-[[[5-fluoro-6-[(2S,4S)- 4-fluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

242		2-[4-[[[5-fluoro-6-[(2S,4R)-4- fluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide AND 2-[4-[[[5-fluoro-6-[(2R,4S)-4- fluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

243		2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethoxy)phenyl] morpholin-4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl]acetic acid

244		2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]-N-methyl- acetamide

245		2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] acetamide

246		5-fluoro-N-[[4-(1H-tetrazol-5- ylmethyl)phenyl]methyl]-6-[(3S)-3- [4-(trifluoromethoxy)phenyl] morpholin-4-yl]pyrimidin-4-amine

247		5-fluoro-N-(tetrahydropyran-4- ylmethyl)-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

248		2-[4-[[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

249		1-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl] cyclopentanecarboxamide

250		1-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- N,N-dimethyl- cyclopentanecarboxamide

251		N-[2-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclopentyl] methanesulfonamide

252		2-[4-[[4-[(3S)-3-[4- (trifluoromethoxy)phenyl] morpholin-4-yl]pyrrolo[2,3-d] pyrimidin-7- yl]methyl]phenyl]acetamide

253		5-fluoro-N-[[4- (methylsulfonylmethyl) tetrahydropyran-4-yl]methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

254		methyl 4-[[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran- 4-carboxylate

255		4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- carboxamide

256		N-(2-aminoethyl)-4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- carboxamide

257		4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- carbonitrile

258		2-[4-[[[5-fluoro-6-[(3S)-3-[2-fluoro- 4-(trifluoromethoxy)phenyl] morpholin-4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

259		6-[4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-N-(tetrahydropyran- 4-ylmethyl)pyrimidin-4-amine

260		6-[4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-N-[[4- (methylsulfonylmethyl) tetrahydropyran-4-yl] methyl]pyrimidin-4-amine

261		[3-[[[6-[4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-pyrimidin-4- yl]amino]methyl]oxetan-3- yl]methanol

262		1-[4-fluoro-4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- 1-piperidyl]ethanone

263		5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]-N-[[1- (trifluoromethylsulfonyl)-4- piperidyl]methyl]pyrimidin-4-amine

264		5-fluoro-N-[(4- fluorotetrahydropyran-4-yl)methyl]- 6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

265		2-[4-[[4-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5,6-dihydropyrrolo[2,3- d]pyrimidin-7- yl]methyl]phenyl]acetamide

266		5-fluoro-N-[(4-fluoro-1- methylsulfonyl-4-piperidyl)methyl]- 6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

267		N-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethoxy)phenyl] morpholin-4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] methanesulfonamide

268		4-[[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- carboxylic acid

273		N-cyclopropyl-4-[[[5-fluoro-6-(3- phenylmorpholin-4-yl)pyrimidin-4- yl]amino]methyl] benzenesulfonamide

274		5-fluoro-N-[(1-methylsulfonyl-4- piperidyl)methyl]-6-(3- phenylmorpholin-4-yl)pyrimidin-4- amine

276		2-[4-[[[5-fluoro-6-(3- phenylmorpholin-4-yl)pyrimidin-4- yl]amino]methyl]phenyl]acetic acid

279		2-[4-[[[5-fluoro-6-(2- phenylpyrrolidin-1-yl)pyrimidin-4- yl]amino]methyl]phenyl]acetamide

280		2-[4-[[[5-fluoro-6-[4-oxo-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

282		2-[5-[[[5-fluoro-6-(3- phenylmorpholin-4-yl)pyrimidin-4- yl]amino]methyl]-2-thienyl]acetic acid

283		2-[5-[[[5-fluoro-6-(3- phenylmorpholin-4-yl)pyrimidin-4- yl]amino]methyl]-2- thienyl]acetamide

284		2-[4-[[4-(3-phenylmorpholin-4- yl)pyrrolo[2,3-d]pyrimidin-7- yl]methyl]phenyl]acetamide

285		2,2,2-trifluoro-N-[4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl] cyclohexyl]ethane sulfonamide

286		4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- N-methyl-tetrahydropyran-4- carboxamide

287		2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] acetonitrile

288		5-fluoro-N-[[4-(1H-tetrazol-5- ylmethyl)cyclohexyl]methyl]-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

290		(3S)-4-[7-[(1-methylsulfonyl-4- piperidyl)methyl]pyrrolo[2,3- d]pyrimidin-4-yl]-3-[4- (trifluoromethoxy)phenyl] morpholine

291		1,1,1-trifluoro-N-[4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl] methanesulfonamide

292		N-cyano-2-[4-[[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

293		5-fluoro-N-[(6-methylsulfonyl-3- pyridyl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

294		N-(2,2-dimethyl-4-methylsulfonyl- butyl)-5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

295		2-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- 2-methyl-cyclohexanol

296		[1-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclopropyl] methanol

297		N-[1-[5-fluoro-6-[(3 S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]-4- piperidyl]methanesulfonamide

299		2-[4-[[[6-[2-(1,3-benzodioxol-5- yl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4- yl]amino]methyl]phenyl]acetamide

300		2-[4-[[[5-fluoro-6-[2-(4- hydroxyphenyl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

301		2-[4-[[[6-[2-(4- ethoxyphenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide

302		2-[4-[[[5-fluoro-6-[2-(p- tolyl)pyrrolidin-1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

303		2-[4-[[[5-fluoro-6-[2-(4- isopropylphenyl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

304		2-[4-[[[5-fluoro-6-[2-(3- methoxyphenyl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

305		2-[4-[[[6-[2-(3- bromophenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide

306		2-[4-[[[6-[2-(3- chlorophenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide

307		2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]azetidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

308		2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]-1- piperidyl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

309		5-fluoro-N-[(4- methylsulfonylmorpholin-2- yl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

310		2-[4-[[[6-[2-(1,3-benzothiazol-2- yl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4- yl]amino]methyl]phenyl]acetamide

311		2-[4-[[[5-fluoro-6-[2-(1- naphthyl)pyrrolidin-1-yl]pyrimidin- 4- yl]amino]methyl]phenyl] acetamide

312		2-[4-[[[5-fluoro-6-[2-(2- naphthyl)pyrrolidin-1-yl]pyrimidin- 4-yl]amino]methyl]phenyl] acetamide

313		2-[4-[[[5-fluoro-6-[2-(5-methyl-2- furyl)pyrrolidin-1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

314		2-[4-[[[5-fluoro-6-[2-(5-methyl- 1,2,4-oxadiazol-3-yl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

315		2-[4-[[[5-fluoro-6-[2-(5-methyl- 1,3,4-oxadiazol-2-yl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

316		2-[4-[[[6-[2-(5-ethyl-2- furyl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4- yl]amino]methyl]phenyl]acetamide

317		2-[4-[[[6-[2-(1,3-dimethylpyrazol-4- yl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4- yl]amino]methyl]phenyl]acetamide

318		2-[4-[[[6-[2-(2,4- dimethoxyphenyl)pyrrolidin-1-yl]- 5-fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide

319		4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzenesulfonic acid

320		4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino] methyl]-N-(2- methoxyethyl)benzenesulfonamide

323		2-[4-[[[5-fluoro-6-[2-[2-hydroxy-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide

324		2-[1-[5-fluoro-6-[(1-methylsulfonyl- 4-piperidyl)methylamino]pyrimidin- 4-yl]pyrrolidin-2-yl]-5- (trifluoromethyl)phenol

325		(2R)-2-[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanoic acid

326		2-[4-[[4-[(3S)-3-[6- (trifluoromethyl)-3- pyridyl]morpholin-4-yl]pyrrolo[2,3- d]pyrimidin-7- yl]methyl]phenyl]acetamide

327		5-fluoro-N-[(1- methylsulfonylpyrrolidin-3- yl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine

328		2-[4-[[4-[(3S)-3-[5- (trifluoromethyl)-2- pyridyl]morpholin-4-yl]pyrrolo[2,3- d]pyrimidin-7- yl]methyl]phenyl]acetamide

329		(3S)-4-[7-[(6-methylsulfonyl-3- pyridyl)methyl]pyrrolo[2,3- d]pyrimidin-4-yl]-3-[4- (trifluoromethoxy)phenyl] morpholine

330		(3S)-4-[7-[(5-methylsulfonyl-2- pyridyl)methyl]pyrrolo[2,3- d]pyrimidin-4-yl]-3-[4- (trifluoromethoxy)phenyl] morpholine

In a related aspect there is provided a prodrug of a compound of Formula (I) as described herein.
Pharmaceutical Compositions
In another aspect, the present disclosure relates to a pharmaceutical composition comprising physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof; and a compound of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein. The compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), included in the pharmaceutical composition may also be any compound of the preferred embodiments described above. In another aspect, the present disclosure relates to a pharmaceutical composition comprising physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof; and a compound of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe). Acceptable carriers or diluents, as well as other additives to be combined with a compound of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein to provide a pharmaceutical composition, for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, taste masking agents, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methylacetate-methacrylate copolymer as a derivative of polyvinyl may be used as suspension agents; and plasticizers such as ester phthalates and the like may be used as suspension agents.
The term “pharmaceutical composition” refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Similar, pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic bases, such as ammonia, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like.
The term “carrier” defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.
The term “diluent” defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
The term “physiologically acceptable” defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 18th edition, 1990.
Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
The pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
Pharmaceutical compositions for use as described herein may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. Physiologically compatible buffers include, but are not limited to, Hanks's solution, Ringer's solution, or physiological saline buffer. If desired, absorption enhancing preparations (for example, liposomes), may be utilized.
For transmucosal administration, penetrants appropriate to the barrier to be permeated may be used in the formulation.
Pharmaceutical formulations for parenteral administration, e.g., by bolus injection or continuous infusion, include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit or almond oils, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration by inhalation, the compounds for use as described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
Further disclosed herein are various pharmaceutical compositions well known in the pharmaceutical art for uses that include intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art. Topical ophthalmic compositions may be formulated as a solution in water buffered at a pH of 5.0 to 8.0. Other ingredients that may be desirable to use in the ophthalmic preparations include preservatives (such as benzalkonium chloride, stabilized oxychloro complex, which is sold as Purite™, or stabilized chlorine dioxide), cosolvents (such as polysorbate 20, 60 and 80, Pluronic® F-68, F-84 and P-103, cyclodextrin, or Solutol) and viscosity-building agents (such as polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, or hydroxypropyl cellulose). The compounds disclosed herein may also be used in an intraocular implant as described in U.S. Pat. No. 7,931,909 which is hereby incorporated by reference. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compounds in water-soluble form, such as eyedrops, or in gellan gum (Shedden et al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayer et al., Ophthalmologica, 210(2):101-3 (1996)); ophthalmic ointments; ophthalmic suspensions, such as microparticulates, drug-containing small polymeric particles that are suspended in a liquid carrier medium (Joshi, A., J. Ocul. Pharmacol., 10(1):29-45 (1994)), lipid-soluble formulations (Alm et al., Prog. Clin. Biol. Res., 312:447-58 (1989)), and microspheres (Mordenti, Toxicol. Sci., 52(1):101-6 (1999)); and ocular inserts. All of the above-mentioned references, are incorporated herein by reference in their entireties. Such suitable pharmaceutical formulations for intraocular delivery are most often and preferably formulated to be sterile, isotonic and buffered for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays often prepared to simulate in many respects nasal secretions to ensure maintenance of normal ciliary action. As disclosed in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990), which is incorporated herein by reference in its entirety, and well-known to those skilled in the art, suitable formulations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drug stabilizers. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such aural formulations include glycerin and water.
The compounds disclosed herein may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
Agents intended to be administered intracellularly may be administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external micro-environment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm. The liposome may be coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the desired organ. Alternatively, small hydrophobic organic molecules may be directly administered intracellularly.
Additional therapeutic or diagnostic agents may be incorporated into the pharmaceutical compositions. Alternatively or additionally, pharmaceutical compositions may be combined with other compositions that contain other therapeutic or diagnostic agents.
Uses
The compounds or pharmaceutical compositions disclosed herein as described above may be used to modulate the activity of a retinoic acid receptor-related orphan receptor (ROR), such as a RORα, RORβ and/or RORγ (RORc) receptor. Modulators of RORγ have been reviewed by B. Fauber and S. Magnuson in J. Med. Chem., Feb. 6, 2014, which hereby is incorporated by reference in its entirety. Examples of RORγ receptors are RORγ1 and RORγt receptors. The compounds or pharmaceutical compositions as described above may also display selective modulation of a particular ROR receptor relative to a different ROR receptor. For example, according to some embodiments disclosed herein some compounds or pharmaceutical compositions modulate the activity of an RORγ receptor to a larger extent than they modulate the activity of RORα and/or RORβ receptors.
The compounds or pharmaceutical compositions disclosed herein may also be used to modulate the activity of regulatory T cells (Tregs).
The compounds or pharmaceutical compositions disclosed herein may also be used to modulate the activity of cells producing IL17 in a RORγt dependent manner, for example, γδT cells, Th17 cells and ILC3 cells.
Publications providing useful background information are Arthritis & Rheumatism, 2014, 66, 579-588; Curr Top Microbial Immun, 2014, 378, 171-182; Drug Disc. Today, 2014, May; Nature Rev. Drug Disc. 2012, 11, 763-776, and Nature Rev. Drug Disc., 2014, 13, 197-216, all of which are hereby incorporated by reference in their entirety.
The compounds or pharmaceutical compositions as described herein and above may also be used in therapy or may be used to treat inflammatory, metabolic, oncologic and autoimmune diseases or disorders. Examples of such diseases or disorders are inflammatory, metabolic, oncologic and autoimmune diseases or disorders mediated or affected by IL17 and/or RORγ (RORc). The role of RORγ in the pathogenesis of autoimmune or inflammatory diseases has been disclosed in Immunity 2007, 26, 643-654; Nat. Rev. Immunol. 2006, 6, 205-217; J. Immunol. 2009, 183, 7169-7177; Brain Pathol. 2004, 14, 164-174; Brain 2007, 130, 1089-1104; and Nat Rev. Immunol. 2008, 8, 183-192 all of which are hereby incorporated by reference in their entirety.
More specific examples of diseases or disorders include asthma, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergy, atopic dermatitis, cystic fibrosis, lung allograph rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, Myasthenia Gravis, Guillain-Barre syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance and type II diabetes and cancer.
More specifically, compounds or pharmaceutical compositions having an antagonistic or inverse agonistic effect on RORγ may be used to reduce levels of IL17 and/or other gene products, such as interleukins, and cytokines, regulated RORγ. This may for example be in subjects suffering from for example, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergy, atopic dermatitis, cystic fibrosis, lung allograph rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, Myasthenia Gravis, Guillain-Barre syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance and type II diabetes.
Conversely, compounds or pharmaceutical compositions having an agonistic effect on RORγ may be used to increase IL17 levels. Increasing IL17 levels may be particularly useful in immune compromised conditions or boosting the immune system response for example during infections and in cancer.
Methods of Administration
The compounds or pharmaceutical compositions may be administered to the patient by any suitable means. Non-limiting examples of methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrasternally, or the like, including infusion pump delivery; (d) administration locally such as by injection directly in the renal or cardiac area, e.g., by depot implantation, by intratumoral injection, or by intra-lymph node injection; (e) administration topically; as well as (f) administration to cells ex vivo followed by insertion of said cells into the patient; as deemed appropriate by those of skill in the art for bringing the compound disclosed herein into contact with living tissue.
Pharmaceutical compositions suitable for administration include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including mammal, e.g. human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.
In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication.
Typically, dosages may be between about 10 microgram/kg and 100 mg/kg body weight, preferably between about 100 microgram/kg and 10 mg/kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.
The exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”, which is hereby incorporated herein by reference in its entirety, with particular reference to Ch. 1, p. 1). Typically, the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compounds, a suitable human dosage can be inferred from ED₅₀or ID₅₀values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 2000 mg of each active ingredient, preferably between 1 mg and 500 mg, e.g. 5 to 200 mg. An ocular eye drop may range in concentration between 0.005 and 5 percent. In one embodiment, an eye drop may range between 0.01 and 1 percent, or between 0.01 and 0.3 percent in another embodiment. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of each active ingredient of between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg is used. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each active ingredient up to 1000 mg per day. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range or frequency in order to effectively and aggressively treat particularly aggressive diseases or infections. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
Dosage amount and interval may be adjusted individually to provide plasma or tissue levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
In cases of local or ex vivo administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
The amount of composition administered may be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition, including but not limited to cancer, cardiovascular disease, and various immune dysfunction. Similarly, acceptable animal models may be used to establish efficacy of chemicals to treat such conditions. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, and route of administration, and regime. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
General Remarks
As described above with reference to specific illustrative embodiments, it is not intended to be limited to the specific form set forth herein. Any combination of the above mentioned embodiments should be appreciated as being within the scope of the invention. Rather, the invention is limited only by the accompanying claims and other embodiments than the specific above are equally possible within the scope of these appended claims.
In the claims, the term “comprises/comprising” does not exclude the presence of other species or steps. Additionally, although individual features may be included in different claims, these may possibly advantageously be combined, and the inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. In addition, singular references do not exclude a plurality. The terms “a”, “an”, “first”, “second” etc. do not preclude a plurality. The phrases “at least one” or “one or more” refer to 1 or a number greater than 1, such as to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

EXPERIMENTAL

The following examples are mere examples and should by no mean be interpreted to limit the scope of the invention. Rather, the invention is limited only by the accompanying claims.
General Chemical Procedures
Unless otherwise stated, starting materials were obtained from commercial suppliers, such as (but not limited to); ABchem, ABCR, Alfa Aesar, Anaspec, Anichem, Apollo Scientific, ASDI-Inter, Asiba Pharmatech, Astatech, Bachem, Chem-Impex, ChemCollect, Chembridge, Combi-Blocks, Enamine, Fluka, Fluorochem, Frontier Scientific, HDH Pharma, InFarmatik, InterBioScreen, Life Chemicals, Manchester organics, Matrix, MercaChem, NetChem, Oakwood Chemical, PepTech, Pharmcore, PrincetonBio, Sigma-Aldrich, TRC, Tyger Scientific and Ukrorgsyn. N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and dichloromethane (DCM) were dried over molecular sieves. Analytical HPLC was performed on a Waters Acquity system using a C18 reverse phase column (Merck Chromolith Speedrod RP-18E) with a linear gradient of the binary solvent system water/acetonitrile/formic acid (A: 100/0/0.1% and B: 0/100/0.1%) with a flow rate of 3.0 mL/min and UV detection at 254 nm at room temperature, combined with MS detection on a Waters Micromass QZ Quadrupole Mass Spectrometer instrument using electron spray ionization, or on a Shimadzu Nexera X2 system using a C18 reverse phase column (Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm), with a linear gradient of the binary solvent system water/methanol/formic acid (A: 100/0/0.1% and B: 0/100/0.1%) with a flow rate of 0.78 mL/min and UV detection at 254 nm, combined with MS detecting on a Shimadzu LCMS-2020 Spectrometer instrument using electron spray ionization. Preparative HPLC was performed on a Waters Acquity system using a C18 reverse phase column (Supelco ASCENTIS C18 581358-U, 15 cm×21.2 mm), with a linear gradient of the binary solvent system water/acetonitrile/formic acid (A: 100/0/0.1% and B: 0/100/0.1%) with a flow rate of 15 mL/min and UV detection at 254 nm, combined with MS detection on a Waters Micromass QZ Quadrupole Mass Spectrometer instrument using electron spray ionization. Chiral resolution was performed on a Lux Cellulose2 (250×21 mm) column using a mobile phase of 0.2% diethyamine in hexane/ethanol, with a flow of 20 mL/min and UV detection at 290 nm. ¹H NMR spectra were recorded on a Bruker Avance 300 spectrometer (at 300 MHz), using CD₃OD, CDCl₃, DMSO-d₆or C₆D₆solvents. Chemical shifts are reported in ppm (δ) using residual solvent as an internal standard; CDCl₃: 7.26 ppm; CD₃OD: 3.31; DMSO-d6: 2.50 ppm. Coupling constants (J) are given in Hz.
Synthetic Methods
The compounds disclosed herein may be made by one of the following four general methods. Further, additional guidance for preparing building blocks to be used in providing compounds disclosed herein is present in the co-pending international application PCT/EP2015/067692 also claiming priority from SE 1450920-2 and SE 1451406-1.
A fluorenylmethyloxycarbonyl (Fmoc) protected amino acid was coupled to a Rink resin to produce 1a using the coupling reagents 1-hydroxy-7-azabenzotriazol (HOAt) and N,N′-diisopropylcarbodiimide (DIC) in the presence of a suitable base, e.g. ethyldiisopropylamine (DIPEA), in DCM/DMF (e.g. in a 1:1 ratio). The mixture was agitated at a suitable temperature until complete conversion of the starting materials was observed, typically overnight at room temperature (i.e. 20-25° C.). The Fmoc group was removed from 1a by treatment with a base, e.g. 20% piperidine in DMF for 30 minutes at room temperature, to yield 1b. An aromatic fluorinated building block, e.g. 4,5,6-trifluoro-pyrimidine, was coupled to a compound containing a free amino group in a nucleophilic aromatic substitution reaction to produce 1c. The reaction may for example be done by addition of DIPEA in dimethyl sulfoxide (DMSO) followed by agitation overnight at room temperature. An aromatic nucleophilic substitution reaction was subsequently performed by addition of a compound containing a free amine to 1c, in the presence of a suitable base, to yield 1d. An example the addition of 4-methyl-2-[4-(trifluoromethyl)phenyl]pyrrolidine and DIPEA in DMSO, followed by agitation overnight at elevated temperature, e.g. 80-100° C. The desired compound 1e was obtained by cleavage from the resin upon treatment of 1d with an acid, e.g. 2,2,2-trifluoroethanoic acid (TFA) as an 80% solution in DCM upon stirring for 1 hour at room temperature. The obtained mixture was concentrated in vacuo and purification by e.g. flash column chromatography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc on silica gel.

Use of General Method 1 to Prepare Example No. 37:

A rink amide resin (0.88 g, 0.68 mmol/g, 0.6 mmol) was swelled in dry DMF (8 mL) for 15 minutes. The resin was drained and treated twice with 20% piperidine in DMF (2×8 mL) for 30 minutes each. The resin was drained and washed with DMF (3×8 mL), methanol (2×8 mL), DMF (2×8 mL) and DCM (3×8 mL). The resin was swelled in dry DCM (8 mL) for 15 minutes and drained. A solution of (2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-fluorophenyl)propanoic acid (0.49 g, 1.2 mol) and 1-hydroxy-7-azabenzotriazol (0.16 mg, 1.2 mmol) dissolved in DMF/DCM (1:1, 8 mL) was added, followed by DIPEA (0.31 mL, 3.6 mmol) and DIC (0.19 mL, 1.2 mmol). The reaction was agitated at room temperature overnight, drained and washed with DMF (3×8 mL), MeOH (2×8 mL), DMF (2×8 mL) and DCM (3×8 mL). The resin was swelled in dry DCM (8 mL) for 15 minutes and drained. A solution of acetic anhydride (0.57 mL, 6 mmol) and pyridine (0.97 mL, 12 mmol) dissolved in DCM (8 mL) was added and the mixture was agitated at room temperature for 1 hour. The resin was drained and washed with DCM (3×8 mL), DMF (3×8 mL) and DCM (3×8 mL). The resin was swelled in dry DMSO (8 mL) for 15 minutes and drained. A solution of 4,5,6-trifluoro-pyrimidine (0.16 g, 1.2 mmol) in dry DMSO (6 mL) was added, followed by DIPEA (0.26 mL, 3.0 mmol). The mixture was agitated overnight at room temperature, drained and washed with DCM (3×8 mL), DMF (3×8 mL) and DCM (3×8 mL). The resin was swelled in dry DMSO (8 mL) for 15 minutes and drained. A solution of 4-methyl-2-[4-(trifluoromethyl)phenyl]pyrrolidine (0.28, 1.2 mmol) in dry DMSO (6 mL) was added, followed by DIPEA (0.26 mL, 3.0 mmol). The mixture was agitated overnight at 80° C., drained and washed with DCM (3×8 mL), DMF (3×8 mL) and DCM (3×8 mL). The resin was swelled in dry DCM (8 mL) for 15 minutes and drained. A solution of 80% TFA in dry DCM (8 mL) was added and the mixture was agitated for 1 hour. The filtrate was collected and the treatment repeated once. The resin was washed with acetonitrile (ACN, 8 mL) and the filtrated collected. The pooled filtrates were concentrated in vacuo and purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding (2R)-2-[[5-fluoro-6-[4-methyl-2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]amino]-3-(4-fluorophenyl)propanamide 37 (37 mg, 12% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.70-7.55 (m, 2H), 7.50-7.45 (s, 1H), 7.43-7.36 (m, 2H), 7.33-7.23 (m, 2H), 7.10-7.00 (m, 2H), 5.22-5.18 (m, 1H), 4.67-4.55 (m, 1H), 4.02-3.92 (m, 1H), 3.43-3.38 (m, 1H), 3.05-2.96 (m, 1H), 2.57-2.52 (m, 1H), 2.31-2.28 (m, 1H), 1.35-1.29 (m, 1H), 1.02 (d, J=6.1 Hz, 3H). m/z 506 (M+H).
General method 1 was used to prepare the following example numbers using the shown starting materials:


Ex.		Aromatic fluorinated
No.	Fmoc protected amino acid	building block	Free amine

5	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-[4-(trifluorometh- yl)phenyl]pyrrolidine

6	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,6-difluoropyrimidine	2-[4-(trifluorometh- yl)phenyl]pyrrolidine

9	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(2,4,5- trifluorophenyl)propanoic acid	4,5,6- trifluoropyrimidine	2-pyrrolidin-2-yl- 1,3-benzothiazole

11	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-(2,4- dichlorophenyl)pyr- rolidine

13	9H-fluoren-9-ylmethyl N- [(1R)-1-carbamoyl-3,3- dimethyl-butyl]carbamate	4,5,6-trifluoro-2- (trifluoromethyl) pyrimidine	2-[4- (trifluoromethyl)phenyl]pyr- rolidine

14	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,6-difluoro-5- methyl-pyrimidine	2-[4- (trifluoromethyl)phen- yl]pyrrolidine

15	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,6-difluoro-2,5- dimethyl-pyrimidine	2-[4- (trifluoromethyl)phen- yl]pyrrolidine

17	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(4- methoxyphenyl)propanoic acid	4,5,6- trifluoropyrimidine	2-[4- (trifluoromethyl)phen- yl]pyrrolidine

18	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	4-methyl-2-[4- (trifluoromethyl)phen- yl]pyrrolidine

19	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-(4-tert- butylphen- yl)pyrrolidine

20	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	3-[4- (trifluorometh- yl)phenyl]morp- holine

23	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	6-pyrrolidin-2-ylquinoline

24	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-(2,3-dihydro-1,4- benzodioxin-6- yl)pyrrolidine

34	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4-methyl-pentanoic acid	4,5,6- trifluoropyrimidine	4-methyl-2-[4- (trifluorometh- yl)phenyl]pyr- rolidine

35	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-[2-chloro-4- (trifluorometh- yl)phenyl]pyrrolidine

37	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(4- fluorophenyl)propanoic acid	4,5,6- trifluoropyrimidine	4-methyl-2-[4- (trifluorometh- yl)phenyl]pyr- rolidine

38	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	3-methyl-2-[4- (trifluoromethyl)phen- yl]pyrrolidine

39	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	2,3,4- trifluoropyridine	2-[4- (trifluoromethyl)phen- yl]pyrrolidine

42	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-pyrrolidin-2-yl-5- (trifluoromethyl)pyridine

43	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-pyrrolidin-2-yl-5- (trifluoromethyl)pyridine

51	(2R)-3-tert-butoxy-2-(9H- fluoren-9-ylmethoxycarbonyl- amino)butanoic acid	4,5,6- trifluoropyrimidine	2-[4- (trifluoromethyl)phen- yl]pyrrolidine

52	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 3-tetrahydropyran-4-yl- propanoic acid	4,5,6- trifluoropyrimidine	2-[4- (trifluoromethyl)phen- yl]pyrrolidine

62	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-[4- (trifluoromethyl)phen- yl]pyrrolidine

63	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 3-(2-oxopyrrolidin-3- yl)propanoic acid	4,5,6- trifluoropyrimidine	2-[4- (trifluoromethyl)phen- yl]pyrrolidine

65	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-[2-methoxy-4- (trifluoromethyl)phenyl]pyrrolidine

68	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	3-[4- (trifluoromethoxy)phenyl]morpholine

72	(2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-[3-fluoro-4- (trifluoromethyl)phenyl]pyrrolidine

77	(2R)-2-hydroxy-4- methyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-[4- (trifluoromethyl)phenyl]pyrrolidine

78	(2R)-2-hydroxy-4- methyl-pentanoic acid	4,5,6- trifluoropyrimidine	2-[4- (trifluoromethyl)phenyl]pyrrolidine

A halogenated pyrrolopyrimidine 2b, e.g. 6-chloro-7-deazapurine, was N-alkylated by addition of an alkyl halide 2a, e.g. 4-(bromomethyl)-1,2-dimethoxy-benzene, and an appropriate base in a suitable solvent, e.g. cesium carbonate in dry dioxane or sodium hydride in dry tetrahydrofuran. The mixture was stirred at room temperature until completion of reaction, typically overnight. The reaction may for example be monitored by thin layer chromatography. The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na₂SO₄, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. Nucleophilic aromatic substitution of the halogen on intermediate 2c was achieved upon addition of a building block containing a free amino group, e.g. 2-(4-trifluoromethyl-phenyl)-pyrrolidine, and a suitable base in an appropriate solvent, e.g. cesium carbonate in dry DMSO. The reaction was achieved by microwave irradiation at elevated temperatures for a period of time, e.g. at 100-150° C. for 1 hour. The reaction may for example be monitored by thin layer chromatography. The desired compound 2d was obtained upon work-up, for example by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na₂SO₄, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane.
Use of General Method 2 to Prepare Example No. 69:
6-Chloro-7-deazapurine (77 mg, 0.5 mmol) and 4-(bromomethyl)-1,2-dimethoxy-benzene (127 mg, 0.55 mmol) were dissolved in dry dioxane (5 mL) and cesium carbonate (325 mg, 1.0 mmol) was added. The mixture was stirred overnight at room temperature, concentrated in vacuo, redissolved in water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding 4-chloro-7-(3,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (65 mg, 43% yield).
4-Chloro-7-(3,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (63 mg, 0.21 mmol) and 2-(4-trifluoromethyl-phenyl)-pyrrolidine (45 mg, 0.21 mmol) were dissolved in dry DMSO (4 mL). Cesium carbonate (137 mg, 0.42 mmol) was added, and the mixture was heated at 150° C. for 30 minutes in a microwave reactor. The mixture was poured onto 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC yielding 7-[(3,4-dimethoxyphenyl)methyl]-4-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrrolo[2,3-d]pyrimidine 69 (9 mg, 9% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.22 (s, 1H), 6.97 (s, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 5.62 (s, 1H), 5.22 (s, 2H), 4.30-3.81 (m, 3H), 3.68 (s, 6H), 2.22-1.71 (m, 4H). m/z 483 (M+H).
General method 2 was used to prepare the following example numbers using the shown starting materials:


Ex.	Halogenated
No.	pyrrolopyrimidine	Alkyl halide	Free amine

4	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	3-[(2-bromobutanoyl- amino)methyl]furan-2- carboxylic acid	2-(4-phenylphenyl)pyrrolidine

67	4-chloro-1H- pyrrolo[2,3- d]pyrimidine	4-(bromomethyl)- 1,2-dimethoxy- benzene	2-[4-(trifluoromethyl)phenyl]pyr- rolidine

69	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	4-(bromomethyl)- 1,2-dimethoxy- benzene	2-[4- (trifluoromethyl)phenyl]pyrrolidine

85	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	2-[4-(bromometh- yl)phenyl]acetic acid	2-[4- (trifluoromethyl)phenyl]pyr- rolidine

195	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	2-[4-(bromometh- yl)phenyl]acetic acid	(2R)-2-[4- (trifluoromethyl)phenyl]pyr- rolidine

196	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	2-[4-(chloromethyl)phen- yl]acetamide	(2R)-2-[4- (trifluoromethyl)phenyl]pyr- rolidine

252	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	2-[4-(chloromethyl)phen- yl]acetamide	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine

265	4-chloro-6,7- dihydro-5H- pyrrolo[2,3- d]pyrimidine	2-[4-(chloromethyl)phen- yl]acetamide	(2R)-2-[4- (trifluoromethyl)phenyl]pyr- rolidine

284	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	2-[4-(chloromethyl)phen- yl]acetamide	3-phenylmorpholine

290	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	4-(bromomethyl)-1- methylsulfonyl- piperidine	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine

326	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	2-[4-(chloromethyl)phen- yl]acetamide	(3S)-3-[6-(trifluoromethyl)-3- pyridyl]morpholine

328	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	2-[4-(chloromethyl)phen- yl]acetamide	(3S)-3-[5-(trifluoromethyl)-2- pyridyl]morpholine

329	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	5-(chloromethyl)-2- methylsulfonyl- pyridine	(3S)-3-[4-(trifluoromethoxy)phen- yl]morpholine

330	4-chloro-7H- pyrrolo[2,3- d]pyrimidine	2-(chloromethyl)-5- methylsulfonyl- pyridine	(3S)-3-[4-(trifluoromethoxy)phen- yl]morpholine

Synthesis of Selected Alkyl Halide

2-[4-(Chloromethyl)phenyl]acetamide

To a solution of 2-(4-(hydroxymethyl) phenyl) acetic acid (20 g, 120.48 mmol) in MeOH:toluene (1:1) (200 mL) at 0° C. was added trimethylsilyldiazomethane (TMSCHN₂, 27.51 g, 240 mmol), and the mixture was stirred at room temperature for 16 hours. After completion, the solvent was evaporated and the crude compound was purified by flash CC (Eluent: EtOAc/pet ether, on silica gel) to afford methyl 2-(4-(hydroxymethyl) phenyl) acetate (Compound-2) (18 g, 83%) as an off white solid.
To a solution of methyl 2-(4-(hydroxymethyl) phenyl) acetate (3.4 g, 1.87 mmol) in MeOH (10 vol) was added aqueous NH₃(34 ml), and the mixture was heated at 90° C. for 16 hours in a sealed tube. After completion, the reaction mixture was allowed to room temperature, filtered and concentrated in vacuo to afford 2-(4-(hydroxymethyl) phenyl) acetamide (1.1 g, 35%) as an off white solid.
To a solution of 2-(4-(hydroxymethyl) phenyl) acetamide (2 g, 12.12 mmol), Et₃N (5.1 mL, 36.36 mmol) in DMF (20 mL) was added methane sulfonyl chloride (1.5 mL, 18.18 mmol), and the mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was poured into ice water and filtered the solid to afford 2-(4-(chloromethyl) phenyl) acetamide (1.2 g, 54%) as an off white solid.
A compound containing a free amino or hydroxyl group 3a, e.g. 1-tetrahydropyran-4-ylpropan-2-amine, was coupled to a fluorinated aromatic compound 3b, e.g. 4,5,6-trifluoro-pyrimidine, upon treatment with a suitable base in an appropriate solvent, e.g. DIPEA or cesium carbonate in dry DMSO or dioxane. Conversion to 3c was typically achieved after stirring at room temperature overnight. The reaction may for example be monitored by thin layer chromatography. The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na₂SO₄, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. Subsequent nucleophilic aromatic substitution of 3c with a building block containing a free amino or hydroxyl group can be achieved upon treatment with a suitable base in an appropriate solvent. An example of such treatment is cesium carbonate in dry DMSO, heated under microwave irradiation during a period of time, e.g. at 80-150° C. for 1 hour. The reaction may for example be monitored by thin layer chromatography. The desired compound 3d was obtained upon work-up, for example by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na₂SO₄, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane.
Use of General Method 3 to Prepare Example No. 41:
4,5,6-Trifluoro-pyrimidine (0.27 g, 2.0 mmol) and 2-(4-trifluoromethyl-phenyl)-pyrrolidine (0.43 g, 2.0 mmol) were dissolved in dry DMSO (4 mL) and DIPEA (0.7 mL, 4.0 mmol) was added. The reaction was stirred at room temperature overnight, poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding 4,5-difluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidine (0.58 g, 88% yield).
4,5-difluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidine (0.33 g, 1.0 mmol) and 1-tetrahydropyran-4-ylpropan-2-amine hydrochloride (0.18 g, 1.0 mmol) were dissolved in dry DMSO (2 mL) and cesium carbonate (0.65 g, 2.0 mmol) was added. The reaction was heated in a microwave reactor for 1 hour at 100° C., poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel), yielding 5-fluoro-N-(1-methyl-2-tetrahydropyran-4-yl-ethyl)-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-amine 41 (205 mg, 45% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.90 (s, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 5.40 (d, J=7.8 Hz, 1H), 4.28-4.24 (m, 2H), 4.05-4.00 (m, 1H), 4.00-3.91 (m, 2H), 3.86-3.79 (m, 1H), 3.39-3.25 (m, 2H), 2.39-2.25 (m, 1H), 1.99-1.83 (m, 3H), 1.76-1.64 (m, 2H), 1.41-1.18 (m, 7H). m/z 453 (M+H).
General method 3 was used to prepare the following example numbers using the shown starting materials:


Ex.			Fluorinated
No.	Free amine or alcohol (1)	Free amine or alcohol (2)	aromatic compound

16	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	4-methoxy-4-methyl- pentan-2-amine	4,5,6- trifluoropyrimidine

21	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	3,3-dimethylbutan-1- amine	4,5,6- trifluoropyrimidine

29	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	(2R)-2-amino- 3-(4- methoxyphen- yl)propan-1-ol	4,5,6- trifluoropyrimidine

30	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	(2R)-2-amino-4,4- dimethyl-pentan-1-ol	4,5,6- trifluoropyrimidine

31	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	(2R)-N,4,4-trimethyl-2- (methylamino)pentan- amide	4,5,6- trifluoropyrimidine

33	4-methyl-2-[4- (trifluorometh- yl)phenyl]pyr- rolidine	(2R)-2-amino-4- methyl-pentanoic acid	4,5,6- trifluoropyrimidine

36	2-[2-chloro-4- (trifluoromethyl)phen- yl]pyrrolidine	(2R)-2-amino-4,4- dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine

41	2-[4- (trifluoromethyl)phenyl]pyrrolidine	1-tetrahydropyran-4-ylpropan- 2-amine	4,5,6- trifluoropyrimidine

44	2-[4- (trifluoromethyl)phenyl]pyrrolidine	4-(aminomethyl)benzoic acid	4,5,6- trifluoropyrimidine

45	2-[4- (trifluoromethyl)phenyl]pyrrolidine	3-[[4- (aminomethyl)phenyl]methyl]-5,5- dimethyl-imidazolidine-2,4-dione	4,5,6- trifluoropyrimidine

46	2-[4- (trifluoromethyl)phenyl]pyrrolidine	[4-(aminomethyl)phenyl]methanesulfon- amide	4,5,6- trifluoropyrimidine

48	2-[4- (trifluoromethyl)phenyl]pyrrolidine	[4-(trifluoromethyl)phenyl]methan- amine	4,5,6- trifluoropyrimidine

53	2-[4- (trifluoromethyl)phenyl]pyrrolidine	(3,4- dimethoxyphenyl)methan- amine	4,5,6- trifluoropyrimidine

54	2-[4- (trifluoromethyl)phenyl]pyrrolidine	(2,3- dimethoxyphenyl)methan- amine	4,5,6- trifluoropyrimidine

55	2-[4- (trifluoromethyl)phenyl]pyrrolidine	1-(3,4-dihydro-2H-1,5- benzodioxepin-7-yl)propan-1- amine	4,5,6- trifluoropyrimidine

56	2-[4- (trifluoromethyl)phenyl]pyrrolidine	(4-morpholinophenyl)methanamine	4,5,6- trifluoropyrimidine

57	2-[4- (trifluoromethyl)phenyl]pyrrolidine	[4-(aminomethyl)phenyl]-morpholino- methanone	4,5,6- trifluoropyrimidine

58	2-[4- (trifluoromethyl)phenyl]pyrrolidine	[1-[5- (aminomethyl)-2- pyridyl]-4- piperidyl]methanol	4,5,6- trifluoropyrimidine

59	2-[4- (trifluoromethyl)phenyl]pyrrolidine	[4-(tetrahydrofuran-2-ylmethoxy)phen- yl]methanamine	4,5,6- trifluoropyrimidine

60	2-[4- (trifluoromethyl)phenyl]pyrrolidine	4-[4-(aminomethyl)phenyl]piperazin- 2-one	4,5,6- trifluoropyrimidine

61	2-[4- (trifluoromethyl)phenyl]pyrrolidine	1-[4- (aminomethyl)phenyl]piperidine-3-carboxamide	4,5,6- trifluoropyrimidine

64	2-[4- (trifluoromethyl)phenyl]pyrrolidine	(1R)-3,3-dimethyl-1- morpholin-2-yl-butan-1-amine	4,5,6- trifluoropyrimidine

66	2-[4- (trifluoromethyl)phenyl]pyrrolidine	(6-methyl-3- pyridyl)methanamine	2,3,4- trifluoropyridine

70	2-[4- (trifluoromethyl)phenyl]pyrrolidine	methyl 2-[4- (aminomethyl)phen- yl]acetate	4,5,6- trifluoropyrimidine

71	2-[4- (trifluoromethyl)phenyl]pyrrolidine	1-[2-[(1R)-1-amino-3,3- dimethyl-butyl]morpholin- 4-yl]ethanone	4,5,6- trifluoropyrimidine

73	2-[3-fluoro-4- (trifluoromethyl)phen- yl]pyrrolidine	(6-methyl-3- pyridyl)methanol	4,5,6- trifluoropyrimidine

74	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	(6-methyl-3- pyridyl)methanol	4,5,6- trifluoropyrimidine

80	5-[4- (trifluoromethyl)phenyl]-1H-pyrazole	(2R)-2-hydroxy-4- methyl-pentanamide	4,5,6- trifluoropyrimidine

88	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	4-(aminometh- yl)benzonitrile	4,5,6- trifluoropyrimidine

89	2-[4-(trifluorometh- yl)phenyl]pyrrolidine	(6-methyl-3- pyridyl)methan- amine	4,5,6- trifluoropyrimidine

90	2-(4- methoxyphenyl)pyr- rolidine	(6-methyl-3- pyridyl)methan- amine	4,5,6- trifluoropyrimidine

93	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	(4-methylcyclo- hexyl)methan- amine	4,5,6- trifluoropyrimidine

94	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	[4-(imidazol-1- ylmethyl)phenyl]methan- amine	4,5,6- trifluoropyrimidine

95	2-[4- (trifluoromethyl)phen- yl]pyrrolidine	[4- (methylsulfonylmeth- yl)phenyl]methan- amine	4,5,6- trifluoropyrimidine

96	5-[4- (trifluoromethyl)phen- yl]-1H-triazole	(6-methyl-3- pyridyl)methan- amine	4,5,6- trifluoropyrimidine

97	2-[4- (trifluoromethoxy)phen- yl]pyrrolidine	(6-methyl-3- pyridyl)methan- amine	4,5,6- trifluoropyrimidine

98	2-[4- (trifluoromethyl)phenyl] pyrrolidine	1-[4- (aminomethyl)phenyl]-2- methyl-propan-2-ol	4,5,6- trifluoropyrimidine

99	2-[4- (trifluoromethyl)phenyl] pyrrolidine	(2-methoxy-6-methyl-3- pyridyl)methanamine	4,5,6- trifluoropyrimidine

100	2-[4- (trifluoromethyl)phenyl]pyrrolidine	5-(aminomethyl)pyridin-2-ol	4,5,6- trifluoropyrimidine

104	2-pyrrolidin-2-yl-5- (trifluoromethyl)phenol	(6-methyl-3- pyridyl)methan- amine	4,5,6- trifluoropyrimidine

105	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	(1-methylpyrrol-3- yl)methanamine	4,5,6- trifluoropyrimidine

106	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	(1-methylpyrazol-4- yl)methanamine	4,5,6- trifluoropyrimidine

107	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	(5-methyl-2-furyl)methan- amine	4,5,6- trifluoropyrimidine

108	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	5-(aminomethyl)pyrrolidin- 2-one	4,5,6- trifluoropyrimidine

109	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	4-(aminomethyl)-1-methyl- pyrrolidin-2-one	4,5,6- trifluoropyrimidine

110	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	5-(aminomethyl)-N,N-dimethyl- tetrahydrofuran-2-carboxamide	4,5,6- trifluoropyrimidine

111	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	(4- methoxytetrahydropyran- 4-yl)methanamine	4,5,6- trifluoropyrimidine

112	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	1-[6-(aminomethyl)-2-methyl-3- pyridyl]ethanol	4,5,6- trifluoropyrimidine

113	2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	(2-methoxy-4- pyridyl)methanamine	4,5,6- trifluoropyrimidine

114	2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	(6-methoxy-3- pyridyl)methanamine	4,5,6- trifluoropyrimidine

115	2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	[4-(1,2,4-triazol-1- ylmethyl)phenyl]methan- amine	4,5,6- trifluoropyrimidine

116	2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	1-(6-methoxy- 3-pyridyl)-N- methyl- methanamine	4,5,6- trifluoropyrimidine

120	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	4-(2-aminoethyl)benzoic acid	4,5,6- trifluoropyrimidine

121	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	(3-aminopyrrolidin-1-yl)-(4- pyridyl)methanone	4,5,6- trifluoropyrimidine

122	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	5-(aminomethyl)indolin-2-one	4,5,6- trifluoropyrimidine

123	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	3-methyl-1-(1H-tetrazol- 5-yl)butan-1-amine	4,5,6- trifluoropyrimidine

124	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	1-[[4- (aminomethyl)phenyl]methyl]pyrrolidin- 2-one	4,5,6- trifluoropyrimidine

126	2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	[6-(trifluoromethyl)-3- pyridyl]methanamine	4,5,6- trifluoropyrimidine

128	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	2-[4-(aminomethyl)phenyl]ethanol	4,5,6- trifluoropyrimidine

129	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	4- (aminomethyl)tetrahy- dropyran-4-ol	4,5,6- trifluoropyrimidine

130	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	4-(aminomethyl)-1-cyclopentyl- pyrrolidin-2-one	4,5,6- trifluoropyrimidine

131	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	(4-methoxy-2- pyridyl)methanamine	4,5,6- trifluoropyrimidine

132	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	(6-methyl-2- pyridyl)methanamine	4,5,6- trifluoropyrimidine

134	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	3,9- diazaspiro[4.5]decan- 2-one	4,5,6- trifluoropyrimidine

135	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	1-methyl-4- (methylaminomethyl)pyr- rolidin-2-one	4,5,6- trifluoropyrimidine

136	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	1-(5-ethyl-2-pyridyl)-N-methyl- methanamine	4,5,6- trifluoropyrimidine

137	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	1-[4- (aminomethyl)phenyl]pyrrolidin-2-one	4,5,6- trifluoropyrimidine

138	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	[4-(1H-tetrazol-5-yl)phenyl]methanamine	4,5,6- trifluoropyrimidine

139	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	phenylmethanamine	4,5,6- trifluoropyrimidine

140	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	4-pyridylmethanamine	4,5,6- trifluoropyrimidine

141	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	3-pyridylmethanamine	4,5,6- trifluoropyrimidine

142	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	(3,5-dimethoxyphen- yl)methanamine	4,5,6- trifluoropyrimidine

143	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	1-[3-(aminomethyl)phenyl]pyrrolidin- 2-one	4,5,6- trifluoropyrimidine

144	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	3-(aminomethyl)-N-methyl- benzamide	4,5,6- trifluoropyrimidine

145	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	3-(aminomethyl)-N,N-dimethyl- benzamide	4,5,6- trifluoropyrimidine

146	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	[3-(1,2,4-triazol-1-ylmethyl)phen- yl]methanamine	4,5,6- trifluoropyrimidine

147	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	[3-(methoxymethyl)phenyl]methan- amine	4,5,6- trifluoropyrimidine

148	2-[4-(trifluorometh- yl)phenyl]pyrrolidine	2-[4-(aminometh- yl)cyclohexyl]acetic acid	4,5,6- trifluoropyrimidine

150	(6-methyl-3-pyridyl)methanamine	2-(5-methyl-2- furyl)pyrrolidine	4,5,6- trifluoropyrimidine

151	2-[4- (trifluoromethyl)phenyl]pyrrolidine	cyclobutyl- methanamine	4,5,6- trifluoropyrimidine

152	2-[4- (trifluoromethyl)phenyl]pyrrolidine	(1-methylcyclo- butyl)methanamine	4,5,6- trifluoropyrimidine

154	(2R)-2-[4- (trifluoromethyl)phen- yl]pyrrolidine	tetrahydrofuran-3- ylmethanamine	4,5,6- trifluoropyrimidine

155	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	tetrahydropyran-2- ylmethanamine	4,5,6- trifluoropyrimidine

159	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	tetrahydrothiophen-2- ylmethanamine	4,5,6- trifluoropyrimidine

161	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	(4- methyltetrahydropyran- 4-yl)methanamine	4,5,6- trifluoropyrimidine

164	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	tetrahydrothiopyran-4- ylmethanamine	4,5,6- trifluoropyrimidine

165	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	3-(aminomethyl)tetra- hydrothiophen-3-ol	4,5,6- trifluoropyrimidine

166	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	(4,4- dimethylcyclohexyl)methan- amine	4,5,6- trifluoropyrimidine

167	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	1-(aminomethyl)cyclo- heptanol	4,5,6- trifluoropyrimidine

168	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	(2-methoxycyclohex- yl)methanamine	4,5,6- trifluoropyrimidine

169	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	4-(aminomethyl)tetra- hydrothiopyran-4-ol	4,5,6- trifluoropyrimidine

170	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	(1,1-dioxothiolan-2- yl)methanamine	4,5,6- trifluoropyrimidine

175	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	(2-tert- butyltetrahydropyran-3- yl)methanamine	4,5,6- trifluoropyrimidine

178	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	(4- isopropylcyclohexyl)methanamine	4,5,6- trifluoropyrimidine

181	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	tetrahydrofuran-2- ylmethanamine	4,5,6- trifluoropyrimidine

182	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	4-(aminomethyl)benzenesulfonamide	4,5,6- trifluoropyrimidine

183	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	(6-chloro-3-pyridyl)methanamine	4,5,6- trifluoropyrimidine

184	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	(1,1-dioxothiolan-3- yl)methanamine	4,5,6- trifluoropyrimidine

185	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	3-thienylmethanamine	4,5,6- trifluoropyrimidine

186	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	tetrahydropyran-3- ylmethanamine	4,5,6- trifluoropyrimidine

188	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	[1-(methoxymeth- yl)cyclobutyl]methan- amine	4,5,6- trifluoropyrimidine

189	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	2-[4-(aminomethyl)phenyl]- N-methyl-acetamide	4,5,6- trifluoropyrimidine

190	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	[4-(1H-tetrazol-5- ylmethyl)cyclohex- yl]methanamine	4,5,6- trifluoropyrimidine

191	(2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine	1-[4- (aminomethyl)- 1-piperidyl]ethanone	4,5,6- trifluoropyrimidine

193	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	(1-oxidopyridin-1-ium-3- yl)methanamine	4,5,6- trifluoropyrimidine

194	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	(1-oxidopyridin-1-ium- 4-yl)methanamine	4,5,6- trifluoropyrimidine

197	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	(1-methylsulfonyl-4- piperidyl)methanamine	4,5,6- trifluoropyrimidine

198	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	(3-methyloxetan- 3-yl)methanamine	4,5,6- trifluoropyrimidine

199	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	(2- methyltetra- hydrofuran-2- yl)methanamine	4,5,6- trifluoropyrimidine

200	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	2-(aminomethyl)cyclo- hexanol	4,5,6- trifluoropyrimidine

201	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	(2- methyltetrahy- drothiophen-2- yl)methanamine	4,5,6- trifluoropyrimidine

202	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	(4,4-dioxo-1,4- oxathian-2- yl)methanamine	4,5,6- trifluoropyrimidine

203	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	2-thienyl- methanamine	4,5,6- trifluoropyrimidine

208	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	tetrahydropyran- 4-ylmethanamine	4,5,6- trifluoropyrimidine

209	2-methyl-2-[4- (trifluoromethyl)phen- yl]pyrrolidine	(6-methyl-3- pyridyl)methan- amine	4,5,6- trifluoropyrimidine

210	(2R)-2-[2-fluoro-4- (trifluoromethyl)phen- yl]pyrrolidine	(6-methyl-3- pyridyl)methanamine	4,5,6- trifluoropyrimidine

211	4-methyl-2-[4- (trifluoromethyl)phen- yl]pyrrolidine	(6-methyl-3- pyridyl)methanamine	4,5,6- trifluoropyrimidine

212	4-methoxy-2-[4- (trifluoromethyl)phen- yl]pyrrolidine	(6-methyl-3- pyridyl)methanamine	4,5,6- trifluoropyrimidine

213	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	(5-methyloxazol-2- yl)methanamine	4,5,6- trifluoropyrimidine

214	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	5-(aminomethyl)-1,3,4- oxadiazol-2-ol	4,5,6- trifluoropyrimidine

215	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	1-(5-methyl-1,2,4-oxadiazol- 3-yl)propan-1-amine	4,5,6- trifluoropyrimidine

216	2-[4-(trifluoromethyl)phenyl]pyr- rolidine	5- (aminomethyl)isoxazol-3-ol	4,5,6- trifluoropyrimidine

217	(2R)-2-[4-(trifluorometh- yl)phenyl]pyrrolidine	[3- (aminomethyl)phenyl]methanol	4,5,6- trifluoropyrimidine

218	(2R)-2-[4-(trifluorometh- yl)phenyl]pyrrolidine	cyclopentylmethanamine	4,5,6- trifluoropyrimidine

219	(2R)-2-[4-(trifluorometh- yl)phenyl]pyrrolidine	(4- methylsulfonylphenyl)methanamine	4,5,6- trifluoropyrimidine

220	(2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine	3-(aminometh- yl)tetrahydrofuran- 3-ol	4,5,6- trifluoropyrimidine

221	(2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine	2-[4- (aminomethyl)tetrahydro- pyran-4-yl]ethanol	4,5,6- trifluoropyrimidine

222	(2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine	(1,1-dioxothian-4- yl)methanamine	4,5,6- trifluoropyrimidine

223	(2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine	4-(aminomethyl)-1,1- dioxo-thian-4-ol	4,5,6- trifluoropyrimidine

224	(2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine	4-(aminomethyl)-N- cyclopropyl- benzenesulfonamide	4,5,6- trifluoropyrimidine

225	(2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine	[4- (aminomethyl)cy- clohexyl]methanol	4,5,6- trifluoropyrimidine

226	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	4-(aminometh- yl)benzamide	4,5,6- trifluoropyrimidine

227	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	[4-(aminometh- yl)phenyl]methan- ol	4,5,6- trifluoropyrimidine

228	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	[3- (aminomethyl)oxetan- 3-yl]methanol	4,5,6- trifluoropyrimidine

229	2-methyl-2-[4- (trifluorometh- yl)phenyl]pyrrolidine	2-[4-(aminometh- yl)phenyl]acetamide	4,5,6- trifluoropyrimidine

230	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	2-[4-(aminometh- yl)phenyl]acetamide	4,5,6- trifluoropyrimidine

231	4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidine	2-[4-(aminometh- yl)phenyl]acetamide	4,5,6- trifluoropyrimidine

232	(2R)-2-[2-fluoro-4- (trifluoromethyl)phenyl]pyrrolidine	2-[4-(aminometh- yl)phenyl]acetamide	4,5,6- trifluoropyrimidine

233	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	1-[4- (aminomethyl)- 1-piperid- yl]ethanone	4,5,6- trifluoropyrimidine

234	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	4-(aminomethyl)- 1,1-dioxo-thian-4- ol	4,5,6- trifluoropyrimidine

235	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	(3- methyloxetan-3- yl)methanamine	4,5,6- trifluoropyrimidine

236	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	4-(aminomethyl)-N- cyclopropyl- benzenesulfonamide	4,5,6- trifluoropyrimidine

237	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	(1- methylsulfonyl- 4- piperidyl)methan- amine	4,5,6- trifluoropyrimidine

238	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	3- (aminomethyl)tetra- hydrofuran-3-ol	4,5,6- trifluoropyrimidine

239	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	2-[4- (aminomethyl)tetrahydro- pyran-4-yl]ethanol	4,5,6- trifluoropyrimidine

240	(2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine	[4- (methylsulfonylmethyl)tetra- hydropyran-4-yl]methanamine	4,5,6- trifluoropyrimidine

241	4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidine	2-[4- (aminomethyl)phen- yl]acetamide	4,5,6- trifluoropyrimidine

242	4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidine	2-[4- (aminomethyl)phen- yl]acetamide	4,5,6- trifluoropyrimidine

243	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	2-[4- (aminomethyl)cyclohexyl]acetic acid	4,5,6- trifluoropyrimidine

244	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	2-[4- (aminomethyl)phen- yl]acetamide	4,5,6- trifluoropyrimidine

245	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	2-[4-(aminomethyl)cyclohexyl]acet- amide	4,5,6- trifluoropyrimidine

246	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	[4-(1H-tetrazol-5-ylmeth- yl)phenyl]methanamine	4,5,6- trifluoropyrimidine

247	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	tetrahydropyran- 4- ylmethanamine	4,5,6- trifluoropyrimidine

248	4-methyl-2-[4-(trifluoromethyl)phen- yl]pyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

249	(3S)-3-[4-(trifluoromethyl)phen- yl]morpholine	1-(aminomethyl)cyclo- pentanecarboxamide	4,5,6- trifluoropyrimidine

250	(3S)-3-[4-(trifluoromethyl)phen- yl]morpholine	1-(aminomethyl)- N,N-dimethyl- cyclopentanecarbox- amide	4,5,6- trifluoropyrimidine

251	(3S)-3-[4-(trifluoromethyl)phen- yl]morpholine	N-[2- (aminomethyl)cyclo- pentyl]methanesulfon- amide	4,5,6- trifluoropyrimidine

253	(3S)-3-[4-(trifluoromethyl)phen- yl]morpholine	[4-(methylsulfonyl- methyl)tetrahydro- pyran-4- yl]methanamine	4,5,6- trifluoropyrimidine

254	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	methyl 4- (aminomethyl)tetra- hydropyran-4- carboxylate	4,5,6- trifluoropyrimidine

255	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	4- (aminomethyl)tetra- hydropyran-4- carboxamide	4,5,6- trifluoropyrimidine

256	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	N-(2-aminoethyl)-4- (aminomethyl)tetrahydropyran- 4-carboxamide	4,5,6- trifluoropyrimidine

257	(3S)-3-[4-(trifluoromethyl)phen- yl]morpholine	4- (aminomethyl)tetra- hydropyran-4- carbonitrile	4,5,6- trifluoropyrimidine

258	(3S)-3-[2-fluoro-4- (trifluoromethoxy)phenyl]morpholine	2-[4- (aminomethyl)phen- yl]acetamide	4,5,6- trifluoropyrimidine

259	4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidine	tetrahydropyran- 4-ylmethanamine	4,5,6- trifluoropyrimidine

260	4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidine	[4- (methylsulfonylmeth- yl)tetrahydropyran-4- yl]methanamine	4,5,6- trifluoropyrimidine

261	4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidine	[3- (aminomethyl)oxetan- 3-yl]methanol	4,5,6- trifluoropyrimidine

262	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	1-[4- (aminomethyl)-4- fluoro-1- piperidyl]ethanone	4,5,6- trifluoropyrimidine

263	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	[1-(trifluoromethyl- sulfonyl)-4- piperidyl]methanamine	4,5,6- trifluoropyrimidine

264	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	(4- fluorotetrahy- dropyran-4- yl]methanamine	4,5,6- trifluoropyrimidine

266	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	(4-fluoro-1- methylsulfonyl-4- piperidyl)methanamine	4,5,6- trifluoropyrimidine

267	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	N-[4- (aminomethyl)cyclo- hexyl]methanesul- fonamide	4,5,6- trifluoropyrimidine

268	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	4- (aminomethyl)tetra- hydropyran-4- carboxylic acid	4,5,6- trifluoropyrimidine

273	3- phenylmorpholine	4-(aminomethyl)-N- cyclopropyl- benzenesulfonamide	4,5,6- trifluoropyrimidine

274	3- phenylmorpholine	(1- methylsulfonyl-4- piperidyl)methan- amine	4,5,6- trifluoropyrimidine

276	3- phenylmorpholine	2-[4- (aminomethyl)phen- yl]acetic acid	4,5,6- trifluoropyrimidine

279	2- phenylpyrrolidine	2-[4- (aminomethyl)phen- yl]acetamide	4,5,6- trifluoropyrimidine

280	5-[4- (trifluoromethyl)phenyl]pyrrolidin- 3-one	2-[4- (aminomethyl)phen- yl]acetamide	4,5,6- trifluoropyrimidine

282	3- phenylmorpholine	2-[5-(aminomethyl)-2- thienyl]acetic acid	4,5,6- trifluoropyrimidine

283	3- phenylmorpholine	2-[5-(aminomethyl)-2- thienyl]acetamide	4,5,6- trifluoropyrimidine

285	(3S)-3-[4- (trifluoromethoxy)phenyl]morpholine	AND Enantiomer N-[4- (aminomethyl)cyclohexyl]- 2,2,2-trifluoro- ethanesulfonamide	4,5,6- trifluoropyrimidine

286	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	4-(aminomethyl)-N- methyl-tetrahydropyran- 4-carboxamide	4,5,6- trifluoropyrimidine

287	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	2-[4- (aminomethyl)cyclo- hexyl]acetonitrile	4,5,6- trifluoropyrimidine

288	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	[4-(1H-tetrazol-5- ylmethyl)cyclohex- yl]methanamine	4,5,6- trifluoropyrimidine

291	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	N-[4- (aminomethyl)phenyl]- 1,1,1-trifluoro- methanesulfonamide	4,5,6- trifluoropyrimidine

292	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	2-[4- (aminomethyl)phen- yl]-N-cyano- acetamide	4,5,6- trifluoropyrimidine

293	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	(6- methylsulfonyl- 3-pyridyl)meth- anamine	4,5,6- trifluoropyrimidine

294	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	2,2-dimethyl-4-methylsulfonyl- butan-1-amine	4,5,6- trifluoropyrimidine

295	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	2-(aminomethyl)-2- methyl-cyclohexanol	4,5,6- trifluoropyrimidine

296	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	[1- (aminomethyl)cy- clopropyl]methanol	4,5,6- trifluoropyrimidine

297	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	N-(4- piperidyl)methanesulfonamide	4,5,6- trifluoropyrimidine

299	2-(1,3-benzodioxol-5- yl)pyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

300	4-pyrrolidin-2-ylphenol	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

301	2-(4- ethoxyphenyl)pyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

302	2-(p-tolyl)pyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

303	2-(4- isopropylphenyl)pyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

304	2-(3- methoxyphenyl)pyr- rolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

305	2-(3-bromophenyl)pyr- rolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

306	2-(3-chlorophenyl)pyr- rolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

307	2-[4- (trifluoromethyl)phen- yl]azetidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

308	2-[4-(trifluoromethyl)phen- yl]piperidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

309	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	(4-methylsulfonylmorph- olin-2-yl)methanamine	4,5,6- trifluoropyrimidine

310	2-pyrrolidin-2-yl-1,3- benzothiazole	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

311	2-(1-naphthyl)pyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

312	2-(2- naphthyl)pyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

313	2-(5-methyl-2- furyl)pyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

314	5-methyl-3-pyrrolidin- 2-yl-1,2,4-oxadiazole	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

315	2-methyl-5- pyrrolidin-2-yl- 1,3,4-oxadiazole	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

316	2-(5-ethyl-2- furyl)pyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

317	1,3-dimethyl-4- pyrrolidin-2-yl- pyrazole	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

318	2-(2,4- dimethoxyphenyl)pyr- rolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

319	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	4-(aminomethyl)benzenesulfonic acid	4,5,6- trifluoropyrimidine

320	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	4-(aminomethyl)-N-(2- methoxyethyl)benzenesulfonamide	4,5,6- trifluoropyrimidine

321	2- benzylpyrrolidine	2-[4-(aminomethyl)phenyl]acetamide	4,5,6- trifluoropyrimidine

324	2-pyrrolidin-2-yl-5- (trifluoromethyl)phenol	(1-methylsulfonyl-4- piperidyl)methanamine	4,5,6- trifluoropyrimidine

325	(2R)-2-[4-(trifluorometh- yl)phenyl]pyrrolidine	(2R)-2-amino-4,4- dimethyl-pentanoic acid	4,5,6- trifluoropyrimidine

327	(3S)-3-[4- (trifluoromethyl)phenyl]morpholine	(1- methylsulfonyl- pyrrolidin-3- yl)methanamine	4,5,6- trifluoropyrimidine

Synthesis of Selected Amines

[4-(1H-Tetrazol-5-ylmethyl)cyclohexyl]methanamine

To 4-[(tert-butoxycarbonylamino)methyl]cyclohexanecarboxylic acid (0.84 g, 3.2 mmol) was added slowly solution of a BH₃-THF solution in THF (16 mL, 1M). The reaction was allowed to stir for 2.5 hours, concentrated in vacuo, and the residue was redissolved and stirred with an aq. sodium hydroxide solution (1M, 30 mL) for 20 min. Ethyl acetate was added, and the mixture was allowed to stir for another 10 min. The phases were separated and the EtOAc phase was concentrated in vacuo and the crude product thereof was purified by flash CC (eluent: EtOAc/heptane, on silica gel) yielding tert-butyl N-[[4 (hydroxymethyl)cyclohexyl]methyl]carbamate (0.76 g, quant yield).
Tert-butyl N-[[4-(hydroxymethyl)cyclohexyl]methyl]carbamate (0.60 g, 2.5 mmol) was dissolved in DCM (20 mL) and Et3N (1 mL) and then methanesulfonyl chloride was the added to the solution. The reaction was stirred over night at room temperature whereafter concentration under reduced pressure yielded a solid that was mixed with water and EtOAc. The EtOAc phase was separated and washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo of the EtOAC phase gave a solid that was dissolved dry DMSO (10 mL). Potassium cyanide (0.36 g, 5.5 mmol) was added and the reaction was heated to 90° C. for 4 hours. The crude reaction was poured into water and the resulting mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: EtOAc/heptane, on silica gel) yielding tert-butyl N-[[4-(cyanomethyl)cyclohexyl]methyl]carbamate (0.57 g, 88% yield).
To a solution of tert-butyl N-[[4-(cyanomethyl)cyclohexyl]methyl]carbamate (160 mg, 0.60 mmol) in nitrobenzene was added triethylammonium chloride (160 mg, 1.2 mmol) and sodium azide (91 mg, 1.4 mmol). The resulting mixture was heated to 105° C. for 11 hours using microwave irradiation. Some more sodium azide (40 mg, 0.7 mmol) was added and the reaction was heated for another 45 min at 105° C. with microwave irradiation. The reaction was extracted with water and the water phase was washed with ether, made acidic with IM HCl and extracted with EtOAc. The EtOAc phase was dried using sodium sulfate, filtered and concentrated in vacuo and finally purified by flash CC (eluent: EtOAc/heptane, on silica gel) yielding tert-butyl N-[[4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methyl]carbamate (33 mg, 18% yield).
Tert-butyl N-[[4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methyl]carbamate (33 mg, 0.11 mmol) was dissolved in DCM (2 mL), TFA (1 mL) was added, and the reaction was stirred for 2 hours. Concentration of the reaction mixture yielded [4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methylammonium 2,2,2-trifluoroacetate that was used without further purification. Using an extra equivalent of the base in the General Method 3 gave [4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methanamine in situ during the reaction.

1-Oxidopyridin-1-ium-3-yl)methanamine

Tert-butyl N-(3-pyridylmethyl)carbamate (1.7 g, 8.4 mmol) was dissolved in DCM, meta-chloroperbenzoic acid (6.1 g, 25 mmol, 70%) was added, and the reaction was stirred at room temperature for 3 hours. After concentration in vacuo, the crude product was purified by flash CC (eluent: EtOAc/heptane followed by EtOAc/MeOH/ammonium hydroxide, on silica gel) to yield tert-butyl N-[(1-oxidopyridin-1-ium-3-yl)methyl]carbamate (1.9 g, 97% yield).
Tert-butyl N-[(1-oxidopyridin-1-ium-3-yl)methyl]carbamate (1.9 g, 8.2 mmol) was dissolved in DCM (2 mL) followed by the addition of TFA. The reaction was heated to reflux overnight. After concentration in vacuo the residue was dissolved in a mixture of MEOH and DCM and the solution was then stirred together with Amberlite IRA-67 free base (7 g, washed and dried) for 30 min. The mixture was filtered with DCM and MeOH. Concentration of the filtrate gave 1-oxidopyridin-1-ium-3-yl)methanamine (0.91 g, 91% yield).

1-Oxidopyridin-1-ium-4-yl)methanamine

Tert-butyl N-(4-pyridylmethyl)carbamate (100 mg, 0.48 mmol) was dissolved in DCM, meta-chloroperbenzoic acid (350 mg, 2.2 mmol, 70%) was added, and the reaction was stirred at room temperature for 4 hours. After concentration in vacuo the crude product was purified by flash CC (eluent: EtOAc/heptane followed by ethyl acetate/MeOH/ammonium hydroxide, on silica gel) to yield tert-butyl N-[(1-oxidopyridin-1-ium-4-yl)methyl]carbamate.
Tert-butyl N-[(1-oxidopyridin-1-ium-4-yl)methyl]carbamate (80 mg, 0.64 mmol) was dissolved in DCM followed by the addition of TFA (0.19 mL). The reaction was heated to 60° C. by microwave irradiation for 30 min. After cooling, the solution was then stirred together with Amberlite IRA-67 free base (0.5 g, washed and dried) for 30 min. The mixture was filtered with DCM and MeOH. Concentration of the filtrate yielded 1-oxidopyridin-1-ium-4-yl)methanamine (48 mg, 61% yield).

1-[4-(Aminomethyl)-4-fluoro-1-piperidyl]ethanone

Tert-butyl N-[(4-fluoro-4-piperidyl)methyl]carbamate (232 mg, 1 mmol) was dissolved in 4 mL DCM and trimethylamine (TEA, 160 μL, 1.1 mmol) was added. The mixture was cooled to 0° C. and acetyl chloride (80 μL, 1.1 mmol) was added. The mixture was stirred for 1 hour while returning to room temperature. The mixture was poured into H₂O, extracted with EtOAc, washed with brine, dried over Na₂SO₄, concentrated in vacuo and purified by flash CC (eluent: Heptane/EtOAc, on silica gel) yielding tert-butyl N-[(1-acetyl-4-fluoro-4-piperidyl)methyl]carbamate. The product was dissolved in 2 mL DCM and a solution of 4M HCl in dioxane (2 mL) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated, and the crude 1-[4-(aminomethyl)-4-fluoro-1-piperidyl]ethanone hydrochloride was used in the next step without further purification (180 mg, 86%).

(4-Fluoro-1-methylsulfonyl-4-piperidyl)methanamine

Tert-butyl N-[(4-fluoro-4-piperidyl)methyl]carbamate (232 mg, 1 mmol) was dissolved in 4 mL DCM and TEA (160 μL, 1.1 mmol) was added. The mixture was cooled to 0° C. and methanesulfonyl chloride (90 μL, 1.1 mmol) was added. The mixture was stirred for 1 hour while returning to room temperature. The mixture was poured into H₂O, extracted with EtOAc, washed with brine, dried over Na₂SO₄, concentrated in vacuo and purified by flash CC (eluent: Heptane/EtOAc) yielding tert-butyl N-[(4-fluoro-1-methylsulfonyl-4-piperidyl)methyl]carbamate. The product was dissolved in 2 mL DCM and a solution of 4M HCl in dioxane (2 mL) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated, and the crude (4-fluoro-1-methylsulfonyl-4-piperidyl)methanamine hydrochloride was used in the next step without further purification (162 mg, 61%).

N-[4-(aminomethyl)cyclohexyl]methanesulfonamide

To a solution of tert-butyl (((trans)-4-aminocyclohexyl)methyl)carbamate (2 g, 8.77 mmol) in CH₂Cl₂(20 mL) at −78° C. was added DIPEA (2.26 g, 17.54 mmol), methane sulfonyl chloride (1 g, 8.77 mmol), and the mixture was stirred at room temperature for 4 hours. After completion, the reaction mixture was poured into ice water and extracted with CH₂Cl₂(3×30 mL). The combined extracts were washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na₂SO₄, filtered and evaporated. The crude compound was purified by flash CC (eluent: DCM/MeOH, on silica gel) to afford tert-butyl (((trans)-4-(methylsulfonamido)cyclohexyl)methyl)carbamate (230 mg) as yellow liquid.
To a solution of tert-butyl (((trans)-4-(methylsulfonamido) cyclohexyl)methyl) carbamate (0.23 g, 0.751 mmol) in dioxane (1 mL) was added 4 N HCl in dioxane (2.3 mL), and the mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was evaporated to afford N-((trans)-4-(aminomethyl)cyclohexyl)methanesulfonamide (140 mg, 91%) as an off white solid.

N-[4-(aminomethyl)phenyl]-1,1,1-trifluoro-methanesulfonamide

To a solution of tert-butyl 4-aminobenzylcarbamate (2 g, 9.0 mmol) in CH₂Cl₂(20 mL) at −78° C. was added Et₃N (1.8 g, 18.01 mmol), trifluoromethanesulfonic anhydride (2.54 g, 9.0 mmol), and the mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with CH₂Cl₂(75 mL) and washed with saturated aq. NaHCO₃(40 mL), water (40 mL), brine (30 mL), dried over anhydrous Na₂SO₄, filtered and evaporated. The crude compound was purified by flash CC (Eluent: EtOAc/Pet ether, on silica gel) to afford tert-butyl 4-(trifluoromethylsulfonamido) benzylcarbamate (1.3 g, 41%) as pale yellow solid. N-[4-(aminomethyl)phenyl]-1,1,1-trifluoro-methanesulfonamide was isolated after BOC deprotection, as described for tert-butyl (((trans)-4-(methylsulfonamido) cyclohexyl)methyl) carbamate.

2-[4-(aminomethyl)phenyl]-N-cyano-acetamide

2-[4-[(tert-butoxycarbonylamino)methyl]phenyl]acetic acid (265 mg, 1.0 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (HATU, 380 mg, 1.0 mmol) and cyanamide (42 mg, 1.0 mmol) were dissolved in 5 mL dry DMF, and DIPEA (0.35 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 4 hours, poured into H₂O, extracted with EtOAc, washed with brine, dried over Na₂SO₄, concentrated in vacuo and purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding tert-butyl tert-butyl N-[[4-[2-(cyanoamino)-2-oxo-ethyl]phenyl]methyl]carbamate. The product was dissolved in 2 mL DCM and a solution of 4M HCl in dioxane (2 mL) was added. The mixture was stirred overnight at room temperature, concentrated, and the crude 2-[4-(aminomethyl)phenyl]-N-cyano-acetamide hydrochloride was used in the next step without further purification (120 mg, 53%).
The initial two steps of general method 4 may be performed in accordance with general method 3. The methyl ester 4a was subsequently hydrolyzed to yield 4b, e.g. by treatment with 1M lithium hydroxide in an appropriate solvent combination, e.g. water/tetrahydrofuran/methanol (e.g. in a ratio of 1:1:1). Hydrolysis was typically achieved after stirring at room temperature overnight. The reaction may for example be monitored by thin layer chromatography The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na₂SO₄, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. Amide analogues 4c were prepared by treatment of 4b with ammonium chloride, HOAt, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and DIPEA in an appropriate solvent, e.g. DMF, followed by stirring at room temperature overnight. The reaction may for example be monitored by thin layer chromatography. The desired compound 4c was obtained upon work-up, for example by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na₂SO₄, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane.
Use of General Method 4 to Prepare Example No. 86:
Methyl 2-[5-(hydroxymethyl)pyrimidin-2-yl]acetate (0.36 g, 2.0 mmol) and 4,5,6-trifluoro-pyrimidine (0.27 g, 2.0 mmol) were dissolved in dry DMSO (4 mL) and DIPEA (0.7 mL, 4.0 mmol) was added. The reaction was stirred at room temperature overnight, poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding methyl 2-[5-[(5,6-difluoropyrimidin-4-yl)oxymethyl]pyrimidin-2-yl]acetate (0.39 g, 66% yield).
Methyl 2-[5-[(5,6-difluoropyrimidin-4-yl)oxymethyl]pyrimidin-2-yl]acetate (0.30 g, 1.0 mmol) and 2-(4-trifluoromethyl-phenyl)-pyrrolidine (0.22 g, 1.0 mmol) were dissolved in dry DMSO (2 mL) and cesium carbonate (0.65 g, 2.0 mmol) was added. The reaction was heated in a microwave reactor for 1 hour at 100° C., poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding methyl 2-[5-[[5-fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetate (0.24 g, 49% yield).
Methyl 2-[5-[[5-fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetate (0.20 g, 0.41 mmol) was dissolved in 2M aq. lithium hydroxide/tetrahydrofuran/methanol (1:1:1, 10 mL) and stirred at room temperature overnight. The solvents were removed in vacuo and the residue purified by preparative HPLC yielding 2-[5-[[5-fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetic acid (0.15 g, 76% yield).
2-[5-[[5-Fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetic acid (0.12 g, 0.25 mmol), ammonium chloride (14 mg, 0.25 mmol), HOAt (31 mg, 0.25 mmol), EDC (39 mg, 0.25 mmol) and DIPEA (45 μL, 0.25 mmol) were dissolved in dry DMF (2 mL), and the reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo, redissolved in EtOAc, washed with sat. aq. potassium carbonate, aq. potassium bisulfate (10%) and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash CC (eluent: eluent: DCM/MeOH, on silica gel) yielding 2-[5-[[5-fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetamide 86 (68 mg, 56% yield). ¹H NMR (300 MHz, CD₃OD) δ 8.02 (s, 1H), 7.94-7.83 (m, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 5.32 (d, J=7.7 Hz, 1H), 4.02-3.96 (m, 1H), 3.81-3.52 (m, 4H), 2.38-2.19 (m, 1H), 1.97-1.71 (m, 3H). m/z 477 (M+H).
General method 4 was used to prepare the following example numbers using the shown starting materials:


			Fluorinated
Ex	Free amine or		aromatic
No.	alcohol (1)	Methyl ester	compound

32

40

79

81

83

84

86

87

91

117

118

119

192

204

205

206

207

Table of ¹H NMR and MS Data for example compounds.


Ex.
No.	¹H NMR or MS Data

4	m/z 589 (M + H)
5	¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 1.9 Hz, 1H), 7.56 (d, J = 8.0 Hz,
	2H), 7.28 (d, J = 8.2 Hz, 2H), 6.46 (s, 1H), 5.41 (d, J = 7.9 Hz, 1H), 5.24
	(s, 1H), 4.69 (s, 1H), 4.58 (s, 1H), 4.08-3.99 (m, 1H), 3.83-3.72 (m,
	1H), 2.36 (dt, J = 15.4, 5.7 Hz, 1H), 2.05 (dd, J = 14.6, 3.6 Hz, 1H), 2.01-1.86
	(m, 3H), 1.50 (dd, J = 14.7, 8.7 Hz, 1H), 0.96 (s, 9H).
6	¹H NMR (300 MHz, CD₃OD) δ 8.23 (s, 1H), 8.06-7.92 (m, 1H), 7.75-7.55
	(m, 2H), 7.48-7.29 (m, 2H), 5.44-4.98 (m, 2H), 4.50-4.21 (m,
	1H), 3.95-3.48 (m, 3H), 2.62-2.42 (m, 1H), 2.11-1.90 (m, 3H), 0.94 (s,
	9H).
9	m/z 517 (M + H)
11	m/z 454 (M + H)
13	¹H NMR (300 MHz, CDCl₃) δ 7.57 (dd, J = 8.2, 3.3 Hz, 2H), 7.31 (dd, J =
	8.0, 3.3 Hz, 2H), 5.46-5.30 (m, 1H), 4.69-4.51 (m, 1H), 4.17-4.00 (m,
	1H), 3.91-3.77 (m, 1H), 2.54-2.25 (m, 1H), 2.12-1.87 (m, 4H), 1.64-1.46
	(m, 1H), 1.04-0.77 (m, 9H).
14	m/z 450 (M + H)
15	m/z 464 (M + H)
16	¹H NMR (300 MHz, CDCl₃) δ 7.94 (d, J = 1.8 Hz, 1H), 7.65-7.50 (m,
	2H), 7.35-7.28 (m, 2H), 5.62-5.47 (m, 1H), 5.42 (t, J = 8.8 Hz, 1H),
	4.22-3.94 (m, 2H), 3.89-3.66 (m, 1H), 2.49-2.28 (m, 1H), 2.05-1.82
	(m, 3H), 1.81-1.55 (m, 4H), 1.26 (dd, J = 6.3, 0.8 Hz, 3H), 1.23-1.15
	(m, 4H), 1.11 (s, 2H).
17	¹H NMR (300 MHz, CDCl₃) δ 7.90 (dd, J = 3.2, 1.8 Hz, 1H), 7.63-7.52
	(m, 2H), 7.35-7.25 (m, 2H), 7.23-7.11 (m, 2H), 6.90-6.76 (m, 2H),
	5.41 (d, J = 8.0 Hz, 1H), 5.12-4.96 (m, 1H), 4.83-4.66 (m, 1H), 4.12-3.98
	(m, 1H), 3.79 (s, 3H), 3.20-2.98 (m, J = 6.7 Hz, 2H), 2.46-2.27 (m,
	1H), 2.04-1.83 (m, 3H).
18	¹H NMR (300 MHz, DMSO-d₆) δ 7.71-7.55 (m, 3H), 7.42 (t, J = 9.0 Hz,
	2H), 7.15 (s, 1H), 6.89 (d, J = 6.9 Hz, 1H), 6.63-6.49 (m, 1H), 5.29-5.17
	(m, 1H), 4.53-4.39 (m, 1H), 4.17-3.90 (m, 1H), 3.42 (t, J = 10.0 Hz,
	2H), 2.66-2.53 (m, 1H), 2.41-2.18 (m, 1H), 1.75-1.54 (m, 2H), 1.42-1.28
	(m, 1H), 1.10-0.99 (m, 3H), 0.85 (dd, J = 8.4, 3.7 Hz, 9H).
19	¹H NMR (300 MHz, DMSO-d₆) δ 7.75 (dd, J = 6.4, 1.9 Hz, 1H), 7.30 (dd,
	J = 8.1, 6.1 Hz, 2H), 7.18-7.01 (m, 3H), 6.87 (d, J = 14.0 Hz, 1H), 6.55-6.44
	(m, 1H), 5.30 (d, J = 7.2 Hz, 1H), 4.46 (qd, J = 9.1, 3.4 Hz, 1H), 3.99-3.89
	(m, 1H), 3.73-3.60 (m, 1H), 2.34-2.19 (m, 1H), 1.91-1.50 (m,
	5H), 1.31-1.17 (m, 9H).
20	¹H NMR (300 MHz, DMSO-d₆) δ 7.93-7.83 (m, 1H), 7.71 (dd, J = 8.4,
	2.5 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.22 (s, 1H), 6.93 (d, J = 6.6 Hz, 1H),
	6.84 (d, J = 8.6 Hz, 1H), 5.46 (d, J = 3.3 Hz, 1H), 4.58-4.45 (m, 1H), 4.35-4.26
	(m, 1H), 4.07-3.81 (m, 3H), 3.73-3.60 (m, 1H), 3.50-3.38 (m,
	1H), 1.81-1.55 (m, 2H), 0.88 (d, J = 3.6 Hz, 9H).
21	¹H NMR (300 MHz, CDCl₃) δ 7.95 (s, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.29
	(d, J = 7.4 Hz, 2H), 5.41 (d, J = 8.2 Hz, 1H), 4.44 (s, 1H), 4.12-3.96 (m,
	1H), 3.88-3.69 (m, 1H), 3.53-3.31 (m, 2H), 2.48-2.28 (m, 1H), 2.06-1.81
	(m, 3H), 1.56-1.40 (m, 2H), 0.95 (s, 9H).
23	m/z 437 (M + H)
24	m/z 444 (M + H)
29	¹H NMR (300 MHz, DMSO-d₆) δ 7.74-7.59 (m, 3H), 7.39 (d, J = 8.0 Hz,
	2H), 7.10 (t, J = 8.0 Hz, 2H), 6.78 (dd, J = 8.4, 6.2 Hz, 2H), 6.46-6.31 (m,
	1H), 5.34 (d, J = 7.7 Hz, 1H), 4.72 (t, J = 5.3 Hz, 1H), 4.21-4.07 (m, 1H),
	4.02-3.86 (m, 1H), 3.68 (s, 3H), 2.88-2.58 (m, 2H), 2.41-2.21 (m, 1H),
	1.98-1.68 (m, 3H), 1.05 (t, J = 7.0 Hz, 1H).
30	¹H NMR (300 MHz, DMSO-d₆) δ 7.77-7.58 (m, 3H), 7.46-7.32 (m,
	2H), 6.29 (d, J = 8.6 Hz, 1H), 5.41-5.29 (m, 1H), 4.70-4.53 (m, 1H),
	4.24-4.08 (m, 1H), 4.02-3.88 (m, 1H), 3.76-3.60 (m, 1H), 2.44-2.23
	(m, 1H), 2.01-1.70 (m, 3H), 1.55-1.33 (m, 2H), 0.90-0.78 (m, 9H).
31	m/z 482 (M + H)
32	¹H NMR (300 MHz, CD₃OD) δ 7.72 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.38
	(d, J = 8.1 Hz, 2H), 7.32-7.17 (m, 4H), 5.49-5.37 (m, 1H), 4.61-4.45
	(m, 2H), 4.13-3.96 (m, 1H), 3.90-3.72 (m, 1H), 3.57 (s, 2H), 2.54-2.35
	(m, 1H), 2.08-1.85 (m, 3H).
33	¹H NMR (300 MHz, CDCl₃) δ 7.94-7.75 (m, 1H), 7.54 (d, J = 8.3 Hz,
	2H), 7.32 (dd, J = 8.4, 2.8 Hz, 2H), 5.27 (t, J = 8.4 Hz, 1H), 4.93-4.79 (m,
	1H), 4.66-4.48 (m, 1H), 4.21-4.04 (m, 1H), 3.53-3.38 (m, 1H), 2.68-2.51
	(m, 1H), 2.48-2.27 (m, 1H), 1.90-1.57 (m, 3H), 1.12 (d, J = 6.4 Hz,
	3H), 1.01-0.84 (m, 6H).
34	¹H NMR (300 MHz, CDCl₃) δ 7.89-7.77 (m, 1H), 7.54 (d, J = 8.1 Hz,
	2H), 7.32 (d, J = 7.9 Hz, 2H), 5.27 (t, J = 8.7 Hz, 1H), 4.91-4.73 (m, 1H),
	4.64-4.47 (m, 1H), 4.24-4.02 (m, 1H), 3.46 (t, J = 10.4 Hz, 1H), 2.71-2.50
	(m, 1H), 2.46-2.29 (m, 1H), 1.89-1.58 (m, 3H), 1.17-1.04 (m,
	3H), 1.01-0.90 (m, 6H).
35	¹H NMR (300 MHz, CDCl₃) δ 7.93 (dd, J = 5.7, 1.9 Hz, 1H), 7.70-7.64
	(m, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.21 (dd, J = 8.1, 5.4 Hz, 1H), 5.59-5.44
	(m, 1H), 4.76-4.68 (m, 1H), 4.64-4.50 (m, 1H), 3.89-3.74 (m, 1H),
	2.52-2.36 (m, 1H), 2.13-1.80 (m, 4H), 1.58-1.43 (m, 1H), 1.02-0.89
	(m, 9H).
36	¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J = 4.1 Hz, 1H), 7.67 (s, 1H), 7.45
	(t, J = 6.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 5.72-5.60 (m, 1H), 4.83-4.70
	(m, 1H), 4.61-4.46 (m, 1H), 4.16-4.02 (m, 1H), 3.92-3.74 (m,
	1H), 2.53-2.36 (m, 1H), 2.12-1.81 (m, 4H), 1.62-1.47 (m, 1H), 1.03-0.93
	(m, 9H).
37	¹H NMR (300 MHz, DMSO-d₆) δ 7.70-7.55 (m, 3H), 7.52-7.45 (m,
	1H), 7.39 (d, J = 7.9 Hz, 2H), 7.35-7.20 (m, 2H), 7.08-6.99 (m, 2H),
	5.29-5.10 (m, 1H), 3.48-3.37 (m, 1H), 2.98 (t, J = 11.9 Hz, 2H), 2.34-2.20
	(m, 1H), 1.41-1.21 (m, 1H), 1.10-0.94 (m, 3H).
38	¹H NMR (300 MHz, CDCl₃) δ 7.95-7.85 (m, 1H), 7.62-7.50 (m, 2H),
	7.35-7.29 (m, 1H), 7.26-7.17 (m, 1H), 5.33-5.23 (m, 1H), 4.15 (t, J =
	9.9 Hz, 1H), 4.03-3.88 (m, 1H), 3.83-3.70 (m, 1H), 1.77-1.62 (m, 3H),
	1.19 (d, J = 6.6 Hz, 2H), 1.01-0.87 (m, 12H).
39	m/z 453 (M + H)
40	¹H NMR (300 MHz, DMSO-d₆) δ 7.70 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.1
	Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.23-7.08 (m, 4H), 6.92-6.75 (m, 1H),
	5.37 (d, J = 7.9 Hz, 1H), 4.56-4.37 (m, 2H), 4.05-3.86 (m, 1H), 3.78-3.61
	(m, 1H), 3.31-3.27 (m, 2H), 2.46-2.22 (m, 2H), 1.97-1.70 (m,
	3H).
41	¹H NMR (400 MHz, CDCl₃) δ 7.90 (S, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.30
	(d, J = 8.6 Hz, 2H), 5.40 (d, J = 7.9 Hz, 1H), 4.25 (s, 2H), 4.07-3.97 (m,
	1H), 3.91 (dd, J = 11.1, 4.3 Hz, 2H), 3.83-3.71 (m, 1H), 3.39-3.26 (m,
	2H), 2.42-2.30 (m, 1H), 2.03-1.85 (m, 3H), 1.69 (d, J = 13.0 Hz, 2H),
	1.49-1.20 (m, 4H), 1.19-1.13 (m, 3H).
42	¹H NMR (400 MHz, DMSO-d₆) δ 8.83-8.77 (m, 1H), 8.11 (d, J = 8.1 Hz,
	1H), 8.05 (d, J = 6.2 Hz, 1H), 7.62-7.55 (m, 1H), 5.59 (s, 1H), 4.67-4.58
	(m, 1H), 4.07 (t, J = 9.7 Hz, 1H), 3.92-3.81 (m, 1H), 2.56 (s, 1H), 2.21-1.95
	(m, 4H), 1.89-1.73 (m, 2H), 0.97-0.87 (m, 9H).
43	¹H NMR (400 MHz, CDCl₃) δ 7.94 (dd, J = 6.4, 2.0 Hz, 1H), 7.03 (dd, J =
	8.6, 4.2 Hz, 2H), 6.93-6.86 (m, 2H), 6.52 (s, 1H), 5.35 (s, 1H), 5.22 (s,
	1H), 4.61 (s, 1H), 4.58-4.48 (m, 1H), 3.98 (s, 1H), 3.73 (t, J = 7.3 Hz,
	1H), 2.38-2.22 (m, 1H), 2.06 (dt, J = 14.5, 3.0 Hz, 1H), 1.98-1.88 (m,
	3H), 1.53-1.42 (m, 1H), 1.32 (dd, J = 5.6, 1.2 Hz, 9H), 0.93 (dd, J = 17.0,
	3.0 Hz, 9H).
44	m/z 461 (M + H)
45	m/z 557 (M + H)
46	m/z 510 (M + H)
48	m/z 485 (M + H)
51	¹H NMR (400 MHz, CDCl₃) δ 7.92 (dd, J = 5.3, 2.0 Hz, 1H), 7.55 (t, J =
	7.6 Hz, 2H), 7.26 (s, 2H), 6.23 (s, 1H), 5.45-5.31 (m, 2H), 5.18 (dd, J =
	7.6, 2.3 Hz, 1H), 4.54-4.45 (m, 1H), 4.14-3.99 (m, 2H), 3.84-3.73 (m,
	1H), 2.45-2.31 (m, 1H), 2.04-1.85 (m, 3H), 1.21 (d, J = 6.4 Hz, 3H),
	1.16 (d, J = 22.8 Hz, 9H).
52	¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (d, J = 8.6 Hz, 1H), 7.66 (dd, J =
	8.5, 2.7 Hz, 2H), 7.46-7.39 (m, 2H), 7.34-7.29 (m, 1H), 6.95 (d, J = 11.9
	Hz, 1H), 6.77 (d, J = 20.9 Hz, 1H), 5.38 (s, 1H), 4.52-4.37 (m, 1H), 3.97
	(d, J = 8.1 Hz, 1H), 3.83-3.67 (m, 3H), 3.29-3.09 (m, 2H), 2.40-2.30
	(m, 1H), 1.98-1.74 (m, 3H), 1.73-1.46 (m, 5H), 1.25-1.05 (m, 2H).
53	m/z 477 (M + H)
54	m/z 477 (M + H)
55	m/z 517 (M + H)
56	m/z 502 (M + H)
57	m/z 530 (M + H)
58	m/z 531 (M + H)
59	m/z 517 (M + H)
60	m/z 515 (M + H)
61	m/z 543 (M + H)
62	¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 1.9 Hz, 1H), 7.56 (d, J = 8.0 Hz,
	2H), 7.28 (d, J = 8.2 Hz, 2H), 6.46 (s, 1H), 5.41 (d, J = 7.9 Hz, 1H), 5.24
	(s, 1H), 4.69 (s, 1H), 4.58 (s, 1H), 4.08-3.99 (m, 1H), 3.83-3.72 (m,
	1H), 2.36 (dt, J = 15.4, 5.7 Hz, 1H), 2.05 (dd, J = 14.6, 3.6 Hz, 1H), 2.01-1.86
	(m, 3H), 1.50 (dd, J = 14.7, 8.7 Hz, 1H), 0.96 (s, 9H).
63	¹H NMR (400 MHz, CDCl₃) δ 7.88 (dd, J = 5.1, 2.0 Hz, 1H), 7.54 (d, J =
	8.6 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 22.7 Hz, 1H), 6.71 (d, J =
	3.7 Hz, 1H), 6.41 (s, 0H), 5.61 (d, J = 8.8 Hz, 1H), 5.47-5.29 (m, 2H),
	4.81-4.56 (m, 1H), 4.09-3.98 (m, 1H), 3.84-3.71 (m, 1H), 3.44-3.28
	(m, 2H), 2.59-2.47 (m, 1H), 2.46-2.29 (m, 2H), 2.25-2.10 (m, 1H),
	2.09-1.81 (m, 6H).
64	¹H NMR (300 MHz, DMSO-d₆) δ 7.73 (dd, J = 7.1, 2.0 Hz, 1H), 7.64 (t, J =
	7.3 Hz, 2H), 7.41 (dd, J = 7.8, 3.7 Hz, 2H), 6.51-6.22 (m, 1H), 5.35 (d,
	J = 7.5 Hz, 1H), 4.21 (s, 1H), 3.96 (s, 1H), 3.69 (d, J = 10.0 Hz, 2H), 3.35
	(s, 1H), 3.27-3.05 (m, 1H), 2.69 (d, J = 11.7 Hz, 1H), 2.64-2.52 (m,
	2H), 2.42-2.14 (m, 3H), 1.99-1.71 (m, 3H), 1.51 (d, J = 11.3 Hz, 1H),
	1.47-1.32 (m, 1H), 0.79 (dd, J = 9.0, 4.2 Hz, 9H).
65	¹H NMR (400 MHz, CDCl₃) δ 7.93 (dd, J = 6.8, 1.7 Hz, 1H), 7.15-6.99
	(m, 3H), 6.44 (s, 1H), 5.60 (d, J = 8.1 Hz, 1H), 5.20 (s, 1H), 4.66-4.51 (m,
	2H), 4.02 (s, 1H), 3.93 (d, J = 2.4 Hz, 3H), 3.75 (t, J = 8.8 Hz, 1H), 2.30 (t,
	J = 7.3 Hz, 1H), 2.09-2.02 (m, 1H), 1.90 (dt, J = 27.6, 9.5 Hz, 3H), 1.47
	(M, 1H), 0.93 (d, J = 17.1 Hz, 9H).
66	m/z 431 (M + H)
67	¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.76 (d, J = 5.6 Hz, 1H),
	7.66 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 7.7 Hz, 2H), 7.17 (d, J = 3.4 Hz, 1H),
	6.96 (s, 1H), 6.82 (dd, J = 8.0, 1.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.44
	(s, 1H), 5.90 (d, J = 5.6 Hz, 1H), 5.31 (d, J = 8.3 Hz, 1H), 5.26-5.14 (m,
	2H), 4.19-4.02 (m, 1H), 3.92-3.76 (m, 1H), 3.70-3.63 (m, 6H), 2.47-2.37
	(m, 1H), 2.09-1.79 (m, 3H).
68	¹H NMR (300 MHz, CDCl₃) δ 7.99 (d, J = 1.7 Hz, 1H), 7.58-7.47 (m,
	2H), 7.22-7.13 (m, 2H), 6.36 (s, 1H), 5.57 (s, 1H), 5.29 (s, 1H), 4.89 (d, J =
	7.5 Hz, 1H), 4.68-4.58 (m, 1H), 4.42-4.31 (m, 1H), 4.08-3.90 (m,
	3H), 3.84-3.69 (m, 1H), 3.50-3.35 (m, 1H), 2.15-2.02 (m, 1H), 1.64-1.56
	(m, 1H), 0.99 (s, 9H).
69	¹H NMR (300 MHz, DMSO-d₆) δ 7.71 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.1
	Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.21-7.10 (m, 5H), 5.37 (d, J = 7.9 Hz,
	1H), 4.55-4.38 (m, 2H), 4.05-3.87 (m, 1H), 3.81-3.65 (m, 1H), 3.64-3.53
	(m, 5H), 2.39-2.21 (m, 1H), 1.99-1.67 (m, 3H).
70	¹H NMR (300 MHz, DMSO-d₆) δ 7.71 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.1
	Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.21-7.10 (m, 5H), 5.37 (d, J = 7.9 Hz,
	1H), 4.55-4.38 (m, 2H), 4.05-3.87 (m, 1H), 3.81-3.65 (m, 1H), 3.64-3.53
	(m, 5H), 2.39-2.21 (m, 1H), 1.99-1.67 (m, 3H).
71	m/z 538 (M + H)
72	¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, J = 5.4 Hz, 1H), 7.52 (q, J = 7.2 Hz,
	1H), 7.10-6.97 (m, 2H), 6.41 (s, 1H), 5.36 (s, 1H), 5.22 (s, 1H), 4.70 (s,
	1H), 4.58 (s, 1H), 4.03 (s, 1H), 3.78 (d, J = 10.8 Hz, 1H), 2.37 (s, 1H), 2.10-1.86
	(m, 4H), 1.52-1.46 (m, 1H), 1.26 (s, 1H), 0.95 (d, J = 11.6 Hz,
	8H).
73	¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J = 2.4 Hz, 1H), 7.96 (s, 1H), 7.66
	(dd, J = 7.8, 2.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H),
	7.05 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 11.0 Hz, 1H), 5.44-5.32 (m, 3H),
	4.06 (dt, J = 6.8, 3.9 Hz, 1H), 3.86-3.76 (m, 1H), 2.55 (s, 3H), 2.45-2.32
	(m, 1H), 2.07-1.87 (m, 3H).
74	¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.65
	(dd, J = 7.9, 2.6 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.28 (s, 2H), 7.14 (d, J =
	7.8 Hz, 1H), 5.46-5.31 (m, 3H), 4.12-4.02 (m, 1H), 3.86-3.77 (m, 1H),
	2.55 (s, 3H), 2.43-2.32 (m, 1H), 2.03-1.87 (m, 3H).
77	¹H NMR (300 MHz, CDCl₃) δ 7.95 (s, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.28
	(d, J = 9.8 Hz, 4H), 6.10 (s, 1H), 5.46 (dt, J = 8.1, 3.4 Hz, 2H), 5.30 (s,
	1H), 4.15-4.01 (m, 1H), 3.92-3.75 (m, 1H), 2.47-2.31 (m, 1H), 2.07-1.72
	(m, 7H), 1.02-0.86 (m, 6H).
78	¹H NMR (300 MHz, CDCl₃) δ 7.93 (s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.26
	(d, 4H), 6.17 (s, 1H), 5.53-5.32 (m, 3H), 4.09 (s, 1H), 3.91-3.78 (m,
	1H), 2.48-2.31 (m, 1H), 2.08-1.48 (m, 7H), 0.92 (dd, J = 7.8, 6.1 Hz,
	6H).
79	¹H NMR (300 MHz, CDCl₃) δ 7.96 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.40
	(d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 4H), 5.47-5.30 (m, 3H), 4.13-4.01
	(m, 1H), 3.88-3.75 (m, 1H), 3.65 (s, 2H), 2.44-2.31 (m, 1H), 2.04-1.85
	(m, 3H).
80	¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 0.3H), 8.77-8.73 (m, 0.64H),
	8.69 (d, J = 2.9 Hz, 0.63H), 8.53 (s, 0.57H), 8.19 (dd, J = 8.1, 2.5 Hz, 2H),
	7.86 (d, J = 8.4 Hz, 2H), 7.61 (s, 0.68H), 7.33 (dd, J = 8.8, 2.8 Hz, 1H),
	7.22 (s, 0.67H), 5.81 (d, J = 6.0 Hz, 0.36H), 5.31 (dd, J = 9.6, 3.7 Hz,
	0.71H), 4.27-4.20 (m, 0.42H), 1.95-1.79 (m, 2H), 1.79-1.66 (m, 1H),
	1.59-1.51 (m, 1H), 1.01-0.89 (m, 6H).
	Note: Due to the presence of isomers the protons were integrated in
	decimals
81	¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.3 Hz,
	2H), 7.31-7.21 (m, 6H), 5.41 (d, J = 7.9 Hz, 1H), 4.93 (s, 1H), 4.66-4.50
	(m, 2H), 4.10-3.98 (m, 1H), 3.86-3.72 (m, 1H), 3.63 (s, 2H), 2.49-2.29
	(m, 1H), 2.03-1.84 (m, 3H).
83	¹H NMR (300 MHz, CDCl₃) δ 8.10 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.46
	(dd, J = 8.3, 2.2 Hz, 4H), 7.37-7.29 (m, 2H), 5.46 (s, 2H), 4.79 (d, J = 6.1
	Hz, 2H), 3.68 (s, 2H).
84	¹H NMR (300 MHz, DMSO-d₆) δ 8.74-8.60 (m, 1H), 8.01-7.84 (m,
	2H), 7.80 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.2 Hz,
	2H), 6.95-6.73 (m, 1H), 5.44 (d, J = 7.7 Hz, 1H), 5.40-5.24 (m, 2H),
	4.17-3.95 (m, 1H), 3.86-3.67 (m, 1H), 3.36 (s, 2H), 2.46-2.29 (m, 1H),
	2.04-1.76 (m, 3H).
85	¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (s, 1H), 8.07 (s, 1H), 7.64 (d, J =
	8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.16 (s, 5H), 6.80-6.55 (m, 1H),
	5.61 (d, J = 7.8 Hz, 1H), 5.44-5.19 (m, 2H), 4.32-4.05 (m, 1H), 4.05-3.78
	(m, 1H), 3.50 (s, 2H), 2.44-2.27 (m, 1H), 2.12-1.70 (m, 3H).
86	¹H NMR (300 MHz, CD₃OD) δ 8.02 (dd, J = 2.3, 1.2 Hz, 1H), 7.93-7.85
	(m, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.32 (d, J = 7.7
	Hz, 1H), 4.81 (d, J = 4.9 Hz, 2H), 4.04-3.92 (m, 1H), 3.72-3.55 (m, 3H),
	2.40-2.19 (m, 1H), 1.95-1.70 (m, 3H).
87	¹H NMR (300 MHz, CD₃OD) δ 7.92 (s, 1H), 7.84-7.79 (m, 1H), 7.65 (t, J =
	1.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.34-5.26
	(m, 1H), 4.39-4.25 (m, 2H), 4.00-3.87 (m, 1H), 3.77-3.60 (m,
	3H), 2.40-2.23 (m, 1H), 1.96-1.73 (m, 3H).
88	¹H NMR (300 MHz, CD₃OD) δ 7.70 (t, J = 1.7 Hz, 1H), 7.67-7.56 (m,
	4H), 7.45 (dd, J = 8.2, 1.6 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 5.47-5.39
	(m, 1H), 4.63 (s, 2H), 4.13-4.00 (m, 1H), 3.86-3.73 (m, 1H), 2.51-2.35
	(m, 1H), 2.06-1.84 (m, 3H).
89	¹H NMR (300 MHz, CD₃OD) δ 8.35 (d, J = 2.2 Hz, 1H), 7.78-7.70 (m,
	1H), 7.65 (dd, J = 8.0, 2.3 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.35 (d, J =
	8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 1H), 5.48-5.36 (m, 1H), 4.55 (d, J = 3.5
	Hz, 2H), 4.13-3.95 (m, 1H), 3.89-3.70 (m, 1H), 2.47 (s, 3H), 2.46-2.31
	(m, 1H), 2.04-1.81 (m, 3H).
90	¹H NMR (300 MHz, CD₃OD) δ 8.39-8.30 (m, 1H), 7.74 (d, J = 1.7 Hz,
	1H), 7.63 (dd, J = 8.0, 2.3 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.07-7.01
	(m, 2H), 6.84-6.77 (m, 2H), 5.36-5.24 (m, 1H), 4.53 (d, J = 3.8 Hz, 2H),
	4.05-3.92 (m, 1H), 3.75-3.64 (m, 5H), 2.47 (s, 3H), 2.36-2.23 (m, 1H),
	1.95-1.82 (m, 3H).
91	¹H NMR (400 MHz, DMSO-d₆) δ 12.20 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H),
	7.63 (q, J = 4.5 Hz, 1H), 7.53-7.47 (m, 2H), 7.33 (d, J = 8.6 Hz, 2H), 7.25-7.14
	(m, 4H), 5.42 (s, 1H), 4.58-4.44 (m, 2H), 4.28 (dd, J = 12.1, 2.3
	Hz, 1H), 4.01-3.81 (m, 3H), 3.65 (td, J = 11.2, 2.9 Hz, 2H), 3.51 (s, 2H),
	3.30-3.24 (m, 1H).
93	¹H NMR (300 MHz, CD₃OD) δ 7.72 (t, J = 2.0 Hz, 1H), 7.58 (d, J = 8.1
	Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 5.44-5.37 (m, 1H), 4.10-3.99 (m, 1H),
	3.84-3.72 (m, 1H), 3.31-3.25 (m, 1H), 3.16 (dd, J = 7.0, 5.2 Hz, 1H),
	2.51-2.34 (m, 1H), 2.04-1.84 (m, 3H), 1.81-1.65 (m, 3H), 1.48-1.38
	(m, 2H), 1.38-1.21 (m, 2H), 1.00-0.82 (m, 6H).
94	¹H NMR (300 MHz, CD₃OD) δ 7.70 (s, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.36
	(d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.06
	(s, 1H), 6.96 (s, 1H), 5.44-5.38 (m, 1H), 4.55 (d, J = 4.7 Hz, 2H), 4.10-3.98
	(m, 1H), 3.85-3.69 (m, 1H), 2.49-2.32 (m, 1H), 2.03-1.82 (m,
	3H).
95	¹H NMR (300 MHz, CD₃OD) δ 7.72 (dd, J = 1.7, 0.7 Hz, 1H), 7.59 (d, J =
	8.1 Hz, 2H), 7.43-7.29 (m, 6H), 5.46-5.39 (m, 1H), 4.65-4.52 (m, 2H),
	4.37 (s, 2H), 4.11-4.00 (m, 1H), 3.80 (dtd, J = 10.4, 7.5, 2.8 Hz, 1H), 2.83
	(s, 3H), 2.52-2.35 (m, 1H), 2.07-1.85 (m, 3H).
96	¹H NMR (300 MHz, DMSO-d₆) δ 9.46 (s, 1H), 8.90 (t, J = 5.9 Hz, 1H),
	8.47 (d, J = 2.5 Hz, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.27 (d, J = 8.2 Hz, 2H),
	7.87 (d, J = 8.6 Hz, 2H), 7.66 (dd, J = 8.0, 2.3 Hz, 1H), 7.22 (d, J = 8.0 Hz,
	1H), 4.67 (d, J = 5.9 Hz, 2H), 2.44 (s, 3H).
97	¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 2.0
	Hz, 1H), 7.53 (dd, J = 8.0, 2.3 Hz, 1H), 7.44-7.34 (m, 1H), 7.33-7.22
	(m, 4H), 7.14 (d, J = 7.9 Hz, 1H), 5.38-5.28 (m, 1H), 4.52-4.36 (m, 2H),
	4.00-3.86 (m, 1H), 3.71-3.62 (m, 1H), 2.40 (s, 3H), 2.36-2.25 (m, 1H),
	2.01-1.66 (m, 3H).
98	¹H NMR (300 MHz, CD₃OD) δ 7.72 (d, J = 1.7 Hz, 1H), 7.60 (d, J = 8.0
	Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.25-7.09 (m, 4H), 5.51-5.37 (m, 1H),
	4.63-4.46 (m, 2H), 4.12-4.00 (m, 1H), 3.86-3.73 (m, 1H), 2.72 (s, 2H),
	2.54-2.38 (m, 1H), 2.04-1.86 (m, 3H), 1.15 (s, 6H).
99	¹H NMR (300 MHz, CD₃OD) δ 7.69 (t, J = 1.4 Hz, 1H), 7.57 (d, J = 8.0
	Hz, 2H), 7.39-7.31 (m, 3H), 6.66 (d, J = 7.3 Hz, 1H), 5.40 (d, J = 7.7 Hz,
	1H), 4.45 (s, 2H), 4.09-3.98 (m, 1H), 3.92 (d, J = 1.2 Hz, 3H), 3.85-3.69
	(m, 1H), 2.50-2.33 (m, 4H), 2.05-1.81 (m, 3H).
100	m/z 434 (M + H)
104	¹H NMR (300 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H),
	7.74 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.9, 2.3 Hz, 1H), 7.44-7.29 (m,
	1H), 7.14 (d, J = 8.0 Hz, 1H), 7.11-6.96 (m, 3H), 5.46 (d, J = 7.9 Hz, 1H),
	4.51-4.33 (m, 2H), 4.04-3.86 (m, 1H), 3.76-3.56 (m, 1H), 2.40 (s, 3H),
	2.31-2.10 (m, 1H), 2.01-1.83 (m, 1H), 1.83-1.60 (m, 2H).
105	m/z 420 (M + H)
106	m/z 421 (M + H)
107	m/z 421 (M + H)
108	m/z 424 (M + H)
109	m/z 438 (M + H)
110	m/z 482 (M + H)
111	m/z 455 (M + H)
112	m/z 476 (M + H)
113	¹H NMR (300 MHz, CD₃OD) δ 7.99 (dd, J = 5.3, 1.0 Hz, 1H), 7.71 (t, J =
	1.3 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 6.86 (dt, J =
	5.4, 1.2 Hz, 1H), 6.67 (s, 1H), 5.43 (d, J = 7.8 Hz, 1H), 4.63-4.46 (m,
	2H), 4.13-3.98 (m, 1H), 3.90-3.75 (m, 4H), 2.52-2.35 (m, 1H), 2.06-1.84
	(m, 3H).
114	¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (dd, J = 2.4, 0.8 Hz, 1H), 7.74 (d, J =
	2.0 Hz, 1H), 7.67-7.60 (m, 2H), 7.59 (d, J = 2.5 Hz, 0H), 7.39 (d, J =
	8.2 Hz, 3H), 6.73 (dd, J = 8.5, 0.8 Hz, 1H), 5.36 (d, J = 7.8 Hz, 1H), 4.48-4.32
	(m, 2H), 3.98-3.90 (m, 1H), 3.79 (s, 3H), 3.76-3.62 (m, 1H), 2.38-2.26
	(m, 1H), 1.97-1.71 (m, 3H).
115	¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (s, 1H), 7.94 (s, 1H), 7.71-7.61
	(m, 3H), 7.46-7.35 (m, 3H), 7.30-7.13 (m, 4H), 5.35 (s, 3H), 4.54-4.33
	(m, 2H), 3.98-3.89 (m, 1H), 3.77-3.61 (m, 1H), 2.42-2.27 (m, 1H),
	1.95-1.70 (m, 3H).
116	¹H NMR (300 MHz, CD₃OD) δ 7.97 (s, 1H), 7.77 (s, 1H), 7.56 (d, J = 8.0
	Hz, 2H), 7.48 (dd, J = 8.8, 1.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 6.69 (d, J =
	8.6 Hz, 1H), 5.46-5.34 (m, 1H), 4.55 (q, J = 15.5 Hz, 2H), 4.11-3.97
	(m, 1H), 3.86 (s, 3H), 3.85-3.68 (m, 1H), 2.95 (d, J = 3.7 Hz, 3H), 2.50-2.34
	(m, 1H), 2.02-1.80 (m, 3H).
117	¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.3 Hz,
	2H), 7.31-7.21 (m, 6H), 5.41 (d, J = 7.9 Hz, 1H), 4.93 (s, 1H), 4.66-4.50
	(m, 2H), 4.10-3.98 (m, 1H), 3.86-3.72 (m, 1H), 3.63 (s, 2H), 2.49-2.29
	(m, 1H), 2.03-1.84 (m, 3H).
118	m/z 475 (M + H)
119	¹H NMR (300 MHz, DMSO-d₆) δ 12.25 (s, 1H), 7.84 (d, J = 1.7 Hz, 1H),
	7.75-7.56 (m, 5H), 7.27-7.11 (m, 4H), 5.46 (s, 1H), 4.51 (d, J = 6.1 Hz,
	2H), 4.30 (dd, J = 12.1, 2.3 Hz, 1H), 4.08-3.81 (m, 4H), 3.66 (td, J = 11.0,
	2.9 Hz, 1H), 3.51 (s, 2H).
120	m/z 475 (M + H)
121	m/z 501 (M + H)
122	m/z 472 (M + H)
123	m/z 465 (M + H)
124	m/z 514 (M + H)
126	¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (s, 1H), 7.95-7.89 (m, 1H), 7.82
	(dd, J = 7.8, 0.7 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H),
	7.54 (t, J = 6.0 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 5.37 (d, J = 8.0 Hz, 1H),
	4.69-4.49 (m, 2H), 4.06-3.91 (m, 1H), 3.80-3.63 (m, 1H), 2.39-2.26
	(m, 1H), 2.02-1.70 (m, 3H).
128	m/z 461 (M + H)
129	m/z 441 (M + H)
130	m/z 492 (M + H)
131	m/z 448 (M + H)
132	m/z 432 (M + H)
134	m/z 464 (M + H)
135	m/z 452 (M + H)
136	m/z 460 (M + H)
137	m/z 500 (M + H)
138	m/z 485 (M + H)
139	m/z 417 (M + H)
140	m/z 418 (M + H)
141	m/z 418 (M + H)
142	m/z 477 (M + H)
143	m/z 500 (M + H)
144	m/z 474 (M + H)
145	m/z 488 (M + H)
146	m/z 498 (M + H)
147	m/z 461 (M + H)
148	m/z 481 (M + H)
150	m/z 368 (M + H)
151	m/z 495 (M + H)
152	m/z 409 (M + H)
154	m/z 411 (M + H)
155	m/z 425 (M + H)
159	m/z 427 (M + H)
161	m/z 439 (M + H)
164	m/z 441 (M + H)
165	m/z 443 (M + H)
166	m/z 451 (M + H)
167	m/z 453 (M + H)
168	m/z 453 (M + H)
169	m/z 457 (M + H)
170	m/z 459 (M + H)
175	m/z 481 (M + H)
178	m/z 465 (M + H)
181	m/z 411 (M + H)
182	m/z 496 (M + H)
183	m/z 452 (M + H)
184	m/z 459 (M + H)
185	m/z 423 (M + H)
186	m/z 425 (M + H)
188	m/z 439 (M + H)
189	m/z 488 (M + H)
190	¹H NMR (300 MHz, CD₃OD) δ 7.71 (s (br), 1H), 7.59 (d, J = 8.1 Hz, 2H),
	7.37 (d, J = 8.1 Hz, 2H), 5.41 (d, J = 7.9 Hz, 1H), 4.14-3.96 (m, 1H),
	3.87-3.72 (m, 1H), 3.28-3.06 (m, 2H), 2.82 (d, J = 6.8 Hz, 2H), 2.57-2.33
	(m, 1H), 2.07-1.85 (m, 3H), 1.85-1.63 (m, 5H), 1.63-1.42 (m, 1H),
	1.17-0.81 (m, 4H).
191	¹H NMR (300 MHz, CD₃OD) δ 7.73 (s (br), Hz, 1H), 7.59 (d, J = 8.0 Hz,
	2H), 7.38 (d, J = 8.0 Hz, 2H), 5.41(d, J = 7.9 Hz, 2H), 4.56-4.42 (m, 1H),
	4.19-3.99 (m, 1H), 3.90 (d, J = 13.8 Hz, 1H), 3.85-3.3.73 (m, 1H), 3.30-3.15
	(m, 2H), 3.13-3.0 (m, 1H), 2.66-2.52 (m, 1H), 2.52-2.36 (m, 1H),
	2.08 (s (br), 3H), 2.05-1.68 (m, 6H), 1.33-0.98 (m, 2H).
192	¹H NMR (300 MHz, cdcl₃) δ 7.96 (d, J = 1.8 Hz, 2H), 7.25 (d, J = 4.5 Hz,
	11H), 7.20-7.09 (m, 4H), 5.38 (d, J = 7.9 Hz, 1H), 4.94 (s, 1H), 4.58 (t, J =
	6.0 Hz, 2H), 4.02 (s, 1H), 3.82-3.70 (m, 1H), 3.63 (s, 2H), 2.40-2.29
	(m, 1H), 2.00-1.84 (m, 3H).
193	¹H NMR (300 MHz, C₆D₆) δ 8.11 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.64 (d,
	J = 6.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.55 (d,
	J = 7.8 Hz, 1H), 6.11 (dd, J = 7.9, 6.4 Hz, 1H), 5.84-5.74 (m, 1H), 5.18
	(d, J = 7.9 Hz, 1H), 4.20-3.99 (m, 2H), 3.92-3.75 (m, 1H), 3.64-3.46
	(m, 1H), 1.89-1.68 (m, 1H), 1.48-1.28 (m, 3H).
194	¹H NMR (300 MHz, DMSO-d₆) δ 8.13-8.07 (m, 2H), 7.72 (d, J = 2.0 Hz,
	1H), 7.69-7.62 (m, 2H), 7.51-7.44 (m, 1H), 7.41 (d, J = 8.1 Hz, 2H),
	7.27-7.20 (m, 2H), 5.38 (d, J = 7.8 Hz, 2H), 4.43 (t, J = 5.5 Hz, 2H), 4.04-3.91
	(m, 2H), 3.77-3.65 (m, 2H), 2.40-2.30 (m, 1H), 1.94-1.75 (m,
	4H).
195	¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (s, 1H), 8.07 (s, 1H), 7.64 (d, J =
	8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.16 (s, 5H), 6.80-6.55 (m, 1H),
	5.61 (d, J = 7.8 Hz, 1H), 5.44-5.19 (m, 2H), 4.32-4.05 (m, 1H), 4.05-3.78
	(m, 1H), 3.50 (s, 2H), 2.44-2.27 (m, 1H), 2.12-1.70 (m, 3H).
196	¹H NMR (300 MHz, DMSO-d₆) δ 7.20 (s, 1H), 6.71 (d, J = 8.1 Hz, 2H),
	6.53 (d, J = 8.1 Hz, 2H), 6.35 (d, J = 8.0 Hz, 2H), 6.24 (d, J = 7.9 Hz, 2H),
	6.13 (s, 1H), 5.60 (s, 1H), 4.78 (d, J = 7.9 Hz, 1H), 4.55-4.35 (m, 2H),
	3.43-3.27 (m, 1H), 3.21-3.03 (m, 1H), 1.74-1.52 (m, 1H), 1.26-1.02
	(m, 3H).
197	¹H NMR (300 MHz, DMSO-d₆) δ 7.73 (s, 1H), 7.64 (d, J = 8.9 Hz, 2H),
	7.43-7.34 (m, 2H), 6.89 (s, 1H), 5.47-5.23 (m, 1H), 4.07-3.88 (m, 1H),
	3.76-3.63 (m, 1H), 3.57-3.46 (m, 2H), 3.27-3.06 (m, 2H), 2.81 (s, 3H),
	2.67-2.54 (m, 2H), 2.42-2.27 (m, 1H), 2.01-1.56 (m, 5H), 1.27-1.01
	(m, 3H).
198	¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.0 Hz,
	2H), 7.29 (d, J = 8.1 Hz, 2H), 5.41 (d, J = 7.9 Hz, 1H), 4.80 (s, 1H), 4.52
	(dd, J = 6.1, 2.1 Hz, 2H), 4.38 (d, J = 6.0 Hz, 2H), 4.08-3.97 (m, 1H),
	3.79-3.70 (m, 1H), 3.68 (dd, J = 13.7, 6.3 Hz, 1H), 3.58 (dd, J = 13.7, 5.9
	Hz, 1H), 2.39-2.36 (m, 1H), 1.97-1.89 (m, 3H), 1.32 (s, 3H).
199	¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 7.9 Hz,
	2H), 7.29 (d, J = 9.3 Hz, 2H), 5.40 (d, J = 7.7 Hz, 1H), 4.92 (s, 1H), 4.03-4.01
	(m, 1H), 3.89-3.72 (m, 3H), 3.52-.3.44 (m, 2H), 2.39-2.35 (m, 1H),
	2.00-1.73 (m, 6H), 1.73-1.58 (m, 1H), 1.20 (d, J = 3.0 Hz, 3H).
200	¹H NMR (300 MHz, CDCl₃) δ 7.84 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 7.9 Hz,
	2H), 7.28 (d, J = 7.9 Hz, 2H), 5.38 (t, J = 7.5 Hz, 1H), 4.99 (s, 1H), 4.76 (s,
	1H), 4.00 (s, 1H), 3.84-3.59 (m, 3H), 3.00-2.90 (m, 1H), 2.3-2.32 (m,
	1H), 2.01-1.81 (m, 4H), 1.77-1.51 (m, 3H), 1.50-1.33 (m, 3H), 1.32-1.21
	(m, 2H).
201	¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 1.8 Hz, 1H), 7.55 (dd, J = 8.4,
	2.2 Hz, 2H), 7.30 (dd, J = 8.5, 2.2 Hz, 2H), 5.41 (d, J = 7.2 Hz, 1H), 5.06
	(s, 1H), 4.04 (s, 1H), 3.77 (td, J = 7.5, 3.2 Hz, 1H), 3.57 (dd, J = 6.1, 3.9
	Hz, 1H), 3.01-2.80 (m, 2H), 2.37 (td, J = 9.6, 8.8, 4.5 Hz, 1H), 2.13-2.00
	(m, 2H), 2.00-1.79 (m, 4H), 1.73-1.68 (m, 1H), 1.42 (s, 3H).
202	¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 7.8 Hz,
	2H), 7.28 (d, J = 8.8 Hz, 2H), 5.40 (d, J = 7.8 Hz, 1H), 4.77 (s, 1H), 4.57-4.42
	(m, 1H), 4.21-4.09 (m, 2H), 4.02-4.01 (m, 1H), 3.85-3.50 (m,
	3H), 3.26-3.13 (m, 2H), 2.38-2.35 (m, 1H), 2.20-2.05 (m, 2H), 1.97-1.89
	(m, 3H).
203	¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 8.1 Hz,
	2H), 7.29-7.26 (m, 2H), 7.20 (dd, J = 5.0, 1.3 Hz, 1H), 6.98 (d, J = 3.3 Hz,
	1H), 6.94-6.92 (m, 1H), 5.40 (d, J = 8.0 Hz, 1H), 4.90-4.66 (m, 2H), 4.03-4.01
	(m, 1H), 3.80-3.75 (m, 1H), 2.37-2.35 (m, 1H), 2.00-1.82 (m,
	3H).
204	¹H NMR (300 MHz, DMSO-d₆) δ 7.84 (d, J = 1.7 Hz, 1H), 7.75-7.55 (m,
	5H), 7.41 (s, 1H), 7.25-7.13 (m, 4H), 6.83 (s, 1H), 5.45 (s, 1H), 4.50 (d, J =
	6.1 Hz, 2H), 4.29 (dd, J = 12.2, 2.3 Hz, 1H), 4.04-3.78 (m, 3H), 3.75-3.59
	(m, 1H).
205	¹H NMR (300 MHz, CDCl₃) δ 7.98 (s, 1H), 7.59 (d, J = 1.4 Hz, 4H), 5.53
	(s, 1H), 4.81 (s, 1H), 4.34 (d, J = 12.0 Hz, 1H), 4.07-3.88 (m, 3H), 3.83-3.71
	(m, 1H), 3.54-3.15 (m, 3H), 2.25 (d, J = 6.5 Hz, 2H), 1.91-1.80 (m,
	5H), 1.09-0.99 (m, 4H).
206	¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J = 1.7 Hz, 1H), 7.62-7.55 (m,
	4H), 5.52 (s, 1H), 5.40-5.21 (m, 2H), 4.80 (s, 1H), 4.33 (dd, J = 11.9, 2.4
	Hz, 1H), 4.06-3.89 (m, 3H), 3.83-3.72 (m, 1H), 3.48-3.35 (m, 1H),
	3.32 (t, J = 6.4 Hz, 2H), 2.10 (d, J = 6.8 Hz, 2H), 1.90-1.78 (m, 5H), 1.52-1.41
	(m, 1H), 1.02 (q, J = 10.5, 10.1 Hz, 4H).
207	¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.27
	(d, J = 8.9 Hz, 2H), 6.80 (dd, J = 20.3, 3.4 Hz, 2H), 5.42 (d, J = 7.8 Hz,
	1H), 5.06 (s, 1H), 4.83-4.50 (m, 2H), 4.05 (m, 1H), 3.80 (s, 3H), 2.38 (q,
	J = 7.5 Hz, 1H), 2.01-1.87 (m, 3H).
208	¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 7.9 Hz,
	2H), 7.34-7.21 (m, 2H), 5.40 (d, J = 7.8 Hz, 1H), 4.61 (s, 1H), 4.07-3.90
	(m, 3H), 3.85-3.69 (m, 1H), 3.43-3.22 (m, 4H), 2.46-2.30 (m, 1H),
	2.03-1.71 (m, 4H), 1.71-1.47 (m, 2H), 1.41-1.17 (m, 3H).
209	¹H NMR (300 MHz, CD₃OD) δ 8.35 (s, 1H), 7.72-7.60 (m, 2H), 7.57 (d,
	J = 8.2 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 4.55 (s,
	2H), 4.10-3.95 (m, 2H), 2.50 (s, 3H), 2.28-2.13 (m, 1H), 2.12-1.83 (m,
	6H).
210	m/z 450 (M + H)
211	m/z 446 (M + H)
212	m/z 462 (M + H)
213	m/z 422 (M + H)
214	m/z 425 (M + H)
215	m/z 451 (M + H)
216	m/z 424 (M + H)
217	m/z 447 (M + H)
218	m/z 409 (M + H)
219	m/z 495 (M + H)
220	¹H NMR (300 MHz, CDCl₃) δ 7.85 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 7.9 Hz,
	2H), 7.28 (d, J = 8.4 Hz, 2H), 5.61 (s, 1H), 5.41 (d, J = 7.9 Hz, 1H), 5.05
	(s, 1H), 4.09-3.70 (m, 5H), 3.64-3.54 (m, 3H), 2.46-2.30 (m, 1H), 2.05-1.86
	(m, 5H).
221	¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.0 Hz,
	2H), 7.30 (d, J = 7.9 Hz, 2H), 5.40 (d, J = 7.9 Hz, 1H), 5.07 (s, 1H), 4.03-4.00
	(m, 1H), 3.82-3.72 (m, 6H), 3.65-3.57 (m, 3H), 3.50 (dd, J = 14.1,
	6.8 Hz, 1H), 2.43-2.31 (m, 1H), 1.98-1.90 (m, 3H), 1.64 (t, J = 5.8 Hz,
	2H), 1.59-1.42 (m, 4H).
222	¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.0 Hz,
	2H), 7.28 (d, J = 8.6 Hz, 3H), 5.39 (d, J = 8.1 Hz, 1H), 4.68 (s, 1H), 4.04-4.01
	(m, 1H), 3.81-3.72 (m, 1H), 3.43-3.33 (m, 2H), 3.09-3.05 (m, 2H),
	2.94 (t, J = 12.5 Hz, 2H), 2.39-2.34 (m, 1H), 2.15 (d, J = 10.4 Hz, 2H),
	1.97-1.85 (m, 6H).
223	¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 8.0 Hz,
	2H), 7.28 (s, 2H), 6.57 (s, 1H), 5.41 (d, J = 7.8 Hz, 1H), 4.95 (s, 1H), 4.05
	(s, 1H), 3.79 (d, J = 7.9 Hz, 1H), 3.59-3.26 (m, 4H), 2.86 (d, J = 13.5 Hz,
	2H), 2.39 (t, J = 7.2 Hz, 1H), 2.21-1.74 (m, 6H).
224	¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 8.0 Hz,
	2H), 7.55 (d, J = 7.8 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.5 Hz,
	2H), 5.46-5.33 (m, 1H), 4.94 (s, 1H), 4.80-4.62 (m, 3H), 4.05-4.01 (m,
	1H), 3.80-3.78 (m, 1H), 2.41-2.36 (m, 1H), 2.23-2.21 (m, 1H), 1.99-1.91
	(m, 3H), 0.70-0.54 (m, 4H).
225	¹H NMR (300 MHz, CDCl₃) δ 7.96 (s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 5.47
	(d, J = 7.9 Hz, 1H), 4.16-4.05 (m, 1H), 3.92-3.79 (m, 1H), 3.49-3.23
	(m, 3H), 2.49-2.34 (m, 1H), 2.12-1.58 (m, 9H), 1.25 (s, 1H), 1.14-0.79
	(m, 4H).
226	m/z 460 (M + H)
227	¹H NMR (300 MHz, CDCl₃) δ 7.87 (s, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.33-7.19
	(m, 6H), 5.37 (d, J = 7.8 Hz, 1H), 4.59 (s, 2H), 4.55 (d, J = 6.0 Hz,
	2H), 4.07-3.94 (m, 1H), 3.83-3.68 (m, 1H), 2.46-2.25 (m, 1H), 2.03-1.80
	(m, 3H).
228	¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 8.0 Hz,
	2H), 7.27 (d, J = 7.2 Hz, 2H), 5.44-5.24 (m, 2H), 4.89 (s, 1H), 4.46-4.31
	(m, 4H), 4.10-3.96 (m, 1H), 3.86-3.66 (m, 5H), 2.46-2.28 (m, 1H),
	2.04-1.85 (m, 3H).
229	¹H NMR (300 MHz, CD₃OD) δ 7.61 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.42
	(d, J = 8.0 Hz, 2H), 4.53 (s, 2H), 4.10-3.96 (m, 2H), 3.48 (s, 2H), 2.26-2.10
	(m, 1H), 2.09-1.82 (m, 6H).
230	¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 1.7 Hz, 1H), 7.52 (d, J = 8.6 Hz,
	2H), 7.35 (d, J = 7.8 Hz, 2H), 7.30-7.24 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H),
	5.53 (s, 1H), 5.32 (s, 2H), 5.03 (s, 1H), 4.67 (d, J = 5.7 Hz, 2H), 4.38-4.29
	(m, 1H), 4.05-3.90 (m, 3H), 3.77 (td, J = 11.2, 2.8 Hz, 1H), 3.58 (s, 2H),
	3.48-3.39 (m, 1H).
231	¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.0 Hz,
	2H), 7.35 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7.4 Hz,
	2H), 5.88-5.49 (m, 1H), 5.31 (s, 2H), 4.94 (s, 1H), 4.72-4.50 (m, 2H),
	4.31 (q, J = 13.0 Hz, 1H), 4.19 (q, J = 12.6 Hz, 1H), 3.57 (s, 2H), 3.16-2.77
	(m, 1H), 2.58-1.97 (m, 1H).
232	¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J = 1.9 Hz, 1H), 7.34-7.28 (m,
	4H), 7.25-7.17 (m, 3H), 5.60 (d, J = 8.2 Hz, 1H), 5.30 (s, 2H), 4.85 (s,
	1H), 4.72-4.39 (m, 2H), 4.20-3.95 (m, 1H), 3.90-3.73 (m, 1H), 3.57 (s,
	2H), 2.55-2.22 (m, 1H), 2.11-1.75 (m, 3H).
233	¹H NMR (300 MHz, CD₃OD) δ 7.86 (s, 1H), 7.65-7.56 (m, 4H), 5.45 (s,
	1H), 4.60-4.46 (m, 1H), 4.30 (dd, J = 12.0, 2.8 Hz, 1H), 4.04-3.84 (m,
	4H), 3.84-3.69 (m, 1H), 3.50-3.36 (m, 2H), 2.83 (s, 2H), 2.36 (t, J = 8.1
	Hz, 1H), 2.13-2.06 (m, 3H), 1.96-1.69 (m, 3H), 1.33-0.98 (m, 2H).
234	¹H NMR (300 MHz, CD₃OD) δ 7.88 (s, 1H), 7.63 (d, J = 1.1 Hz, 4H), 5.53-5.47
	(m, 1H), 4.34 (dd, J = 12.1, 2.5 Hz, 1H), 4.11 (q, J = 7.2 Hz, 1H),
	4.06-3.88 (m, 3H), 3.85-3.70 (m, 1H), 3.52 (s, 2H), 3.50-3.36 (m, 2H),
	2.97-2.86 (m, 2H), 2.15-2.02 (m, 4H).
235	¹H NMR (300 MHz, CD₃OD) δ 7.86 (s, 1H), 7.67-7.58 (m, 4H), 5.49-5.44
	(m, 1H), 4.62 (d, J = 5.9 Hz, 2H), 4.36-4.26 (m, 3H), 4.05-3.87 (m,
	3H), 3.84-3.71 (m, 1H), 3.61 (s, 2H), 3.50-3.38 (m, 1H), 1.33 (s, 3H).
236	¹H NMR (300 MHz, CD₃OD) δ 7.67-7.58 (m, 3H), 7.41 (s, 4H), 7.31 (d,
	J = 8.1 Hz, 2H), 5.34-5.23 (m, 1H), 4.51 (s, 2H), 4.12 (dd, J = 12.0, 2.6 Hz,
	1H), 3.83-3.65 (m, 3H), 3.56 (td, J = 10.8, 2.8 Hz, 1H), 3.29-3.16
	(m, 1H), 1.96-1.88 (m, 1H), 0.34-0.22 (m, 4H).
237	¹H NMR (300 MHz, CD₃OD) δ 7.86 (s, 1H), 7.66-7.59 (m, 4H), 5.47-5.42
	(m, 1H), 4.30 (dd, J = 12.0, 2.9 Hz, 1H), 4.04-3.86 (m, 3H), 3.84-3.68
	(m, 3H), 3.50-3.38 (m, 1H), 2.81 (s, 3H), 2.76-2.63 (m, 2H), 2.02
	(d, J = 0.9 Hz, 1H), 1.92-1.67 (m, 3H), 1.38-1.19 (m, 3H).
238	m/z 443 (M + H)
239	m/z 485 (M + H)
240	m/z 517 (M + H)
241	m/z 492 (M + H)
242	m/z 492 (M + H)
243	m/z 513 (M + H)
244	m/z 504 (M + H)
245	¹H NMR (300 MHz, CDCl₃) δ 7.99 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 8.3 Hz,
	2H), 7.17 (d, J = 8.4 Hz, 2H), 5.50 (s, 1H), 5.41-5.18 (m, 2H), 4.81 (s,
	1H), 4.33 (d, J = 11.8 Hz, 1H), 4.06-3.88 (m, 3H), 3.82-3.71 (m, 1H),
	3.47-3.26 (m, 3H), 2.11 (d, J = 6.8 Hz, 2H), 1.91-1.73 (m, 5H), 1.03 (q,
	J = 10.3, 9.7 Hz, 4H).
246	¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J = 1.6 Hz, 1H), 7.58-7.46 (m,
	2H), 7.27-7.10 (m, 6H), 5.56 (s, 1H), 5.36 (m, 1H), 4.59 (d, J = 5.7 Hz,
	2H), 4.35 (dd, J = 12.0, 2.0 Hz, 1H), 4.24 (s, 2H), 4.08-3.89 (m, 3H), 3.77
	(td, J = 11.2, 2.7 Hz, 1H), 3.49 (s, 1H), 3.43 (m, 1H).
247	¹H NMR (300 MHz, CD₃OD) δ 7.85 (s, 1H), 7.61 (s, 4H), 5.44 (t, J = 3.1
	Hz, 1H), 4.29 (dd, J = 12.1, 2.9 Hz, 2H), 4.00-3.86 (m, 4H), 3.84-3.72
	(m, 1H), 3.50-3.26 (m, 5H), 1.96-1.79 (m, 1H), 1.71-1.62 (m, 2H),
	1.37-1.20 (m, 2H).
248	¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 8.2 Hz,
	2H), 7.36-7.27 (m, 4H), 7.23 (d, J = 8.1 Hz, 2H), 5.28-5.24 (m, 3H), 4.82
	(m, 2H), 4.60 (dd, J = 10.3, 5.7 Hz, 2H), 4.08 (m, 1H), 3.57 (s, 2H), 3.45 (t,
	J = 10.3 Hz, 1H), 2.64-2.51 (m, 1H), 2.36 (m, 1H), 1.52-1.40 (m, 1H),
	1.10 (d, J = 6.6 Hz, 3H).
249	¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J = 1.6 Hz, 1H), 7.58 (s, 4H), 5.94
	(s, 1H), 5.51 (d, J = 17.3 Hz, 2H), 5.39-5.17 (m, 1H), 4.39-4.28 (m,
	1H), 4.07-3.85 (m, 4H), 3.85-3.69 (m, 1H), 3.66 (d, J = 6.0 Hz, 2H),
	3.51-3.30 (m, 1H), 1.98-1.94 (m, 2H), 1.88-1.66 (m, 6H).
250	¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J = 1.6 Hz, 1H), 7.58 (s, 4H), 5.50
	(s, 2H), 4.32 (dd, J = 12.1, 2.3 Hz, 1H), 4.09-3.86 (m, 3H), 3.82-3.68
	(m, 1H), 3.63 (d, J = 5.8 Hz, 2H), 3.48-3.30 (m, 1H), 3.00 (s, 6H), 2.28-1.92
	(m, 2H), 1.94-1.75 (m, 6H).
251	¹H NMR (300 MHz, CDCl₃) δ 7.97 (s, 1H), 7.58 (s, 4H), 5.65-5.39 (m,
	2H), 4.63 (d, J = 8.1 Hz, 1H), 4.39-4.28 (m, 1H), 4.08-3.69 (m, 5H),
	3.61-3.24 (m, 4H), 2.98 (d, J = 2.2 Hz, 3H), 2.33-1.80 (m, 3H), 1.83-1.58
	(m, 3H).
252	¹H NMR (300 MHz, CDCl3): δ 8.46 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.28-7.18
	(m, 6H), 6.97 (d, J = 3.7 Hz, 1H), 6.44 (d, J = 3.7 Hz, 1H), 6.05 (s,
	1H), 5.44-5.35 (m, 3H), 4.55-451 (m, 2H), 4.13-08 (m, 2H), 3.86-3.72
	(m, 1H), 3.60-155 (m, 3H).
253	¹H NMR (300 MHz, CDCl₃): δ 7.94 (d, J = 1.7 Hz, 1H), 7.59 (s, 4H), 5.78
	(m, 1H), 5.55 (s, 1H), 4.35 (dd, J = 12.0, 2.2 Hz, 1H), 4.09-3.83 (m, 7H),
	3.82-3.65 (m, 3H), 3.48-3.35 (m, 1H), 3.13 (s, 2H), 3.00 (s, 3H), 1.87-1.60
	(m, 4H).
254	¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J = 1.7 Hz, 1H), 7.59 (s, 4H), 5.54
	(s, 1H), 5.02 (m, 1H), 4.37-4.32 (m, 1H), 4.04-3.76 (m, 6H), 3.73-3.55 (m,
	5H), 3.55-3.41 (m, 3H), 2.14-2.09 (m, 2H), 1.65-1.55 (m, 2H).
255	¹H NMR (300 MHz, CDCl₃): δ 7.95 (d, J = 1.8 Hz, 1H), 7.59 (s, 4H), 5.88
	(s, 1H), 5.55 (s, 1H), 5.43 (s, 1H), 5.22 (q, J = 5.5 Hz, 1H), 4.37-4.33 (m,
	1H), 4.04-4.63 (m, 10H), 3.46-3.37 (m, 1H), 2.06 (m, 2H), 1.75-1.66 (m,
	2H).
256	¹H NMR (300 MHz, DMSO-d₆) δ 7.96-7.84 (m, 2H), 7.84-7.75 (m,
	1H), 7.72 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 6.87 (s, 1H), 5.44
	(s, 1H), 4.37-4.04 (m, 3H), 4.04-3.81 (m, 4H), 3.61 (dd, J = 42.7, 13.3
	Hz, 5H), 3.40-3.21 (m, 4H), 2.82 (d, J = 6.2 Hz, 2H), 1.95 (d, J = 13.7
	Hz, 2H), 1.48 (t, J = 11.0 Hz, 2H).
257	¹H NMR (300 MHz, CDCl₃): 7.97 (d, J = 1.7 Hz, 1H), 7.60 (s, 4H), 5.59
	(s, 1H), 5.07 (s, 1H), 4.39-4.35 (m, 1H), 4.04-3.93 (m, 5H), 3.80-3.64 (m,
	5H), 3.48-3.38 (m, 1H), 1.89-1.54 (m, 4H).
258	¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, J = 1.6 Hz, 1H), 7.58 (t, J = 8.4 Hz,
	1H), 7.33 (d, J = 7.9 Hz, 2H), 7.26 (s, 2H), 7.00-6.93 (m, 2H), 5.61 (s, 1H),
	5.33 (s, 2H), 5.02 (s, 1H), 4.70-4.61 (m, 2H), 4.20-4.16 (m, 1H), 4.06-3.96
	(m, 3H), 3.81-3.75 (m, 1H), 3.62-3.55 (m, 3H).
259	¹H NMR (300 MHz, CDCl₃): δ 7.89 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.1
	Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 5.60 (m, 1H), 4.73 (s, 1H), 4.32-4.16 (m,
	2H), 3.99-3.94 (m, 2H), 3.40-3.30 (m, 4H), 2.94-2.87 (m, 1H), 2.41-2.35
	(m, 1H), 1.82 (m, 1H), 1.66-1.62 (m, 2H), 1.40-1.26 (m, 2H).
260	¹H NMR (300 MHz, CDCl₃): δ 7.84 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.1
	Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 5.66-5.58 (m, 2H), 4.31-4.15 (m, 2H),
	4.06-3.86 (m, 4H), 3.70-3.66 (m, 2H), 3.09 (s, 2H), 2.98-2.86 (m, 4H),
	2.40-2.34 (m, 1H), 1.80-1.54 (m, 4H), 1.11-0.95 (m, 1H).
261	¹H NMR (400 MHz, CDCl₃): δ 7.84 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.0
	Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.60 (m, 1H), 5.01 (m, 1H), 4.93 (t, J =
	7.3 Hz, 1H), 4.44-4.32 (m, 4H), 4.29-4.15 (m, 2H), 3.86-3.80 (m, 2H), 3.71
	(d, J = 7.1 Hz, 2H), 2.94-2.86 (m, 1H), 2.45-2.34 (m, 1H).
262	¹H NMR (300 MHz, CD₃OD) δ 7.86 (s, 1H), 7.70-7.55 (s, 4H), 5.47 (s,
	1H), 4.38-4.25 (m, 2H), 4.05-3.86 (m, 3H), 3.86-3.55 (m, 4H), 3.53-3.30
	(m, 3H), 2.10 (s, 3H), 1.96-1.48 (m, 4H).
263	¹H NMR (300 MHz, CD₃OD) δ 7.86 (s, 1H), 7.67-7.61 (m, 4H), 5.45 (s,
	1H), 4.31 (dd, J = 12.0, 2.8 Hz, 2H), 4.05-3.88 (m, 5H), 3.85-3.72 (m,
	1H), 3.51-3.35 (m, 2H), 3.16-3.01 (m, 2H), 1.95-1.81 (m, 3H), 1.38-1.20
	(m, 2H).
264	¹H NMR (300 MHz, CD₃OD) δ 7.87 (t, J = 1.3 Hz, 1H), 7.67-7.61 (m,
	4H), 5.47 (s, 1H), 4.06-3.89 (m, 3H), 3.86-3.63 (m, 7H), 3.49-3.38 (m,
	1H), 1.92-1.69 (m, 4H).
265	¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.29
	(d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 5.39
	(d, J = 8.0 Hz, 1H), 5.31 (s, 2H), 4.56-4.44 (m, 2H), 4.01 (t, J = 9.8 Hz,
	1H), 3.79-3.77 (m, 1H), 3.56 (s, 2H), 3.28-3.10 (m, 3H), 2.91-2.63 (m,
	1H), 2.35 (m, 1H), 1.96-1.90 (m, 3H).
266	¹H NMR (300 MHz, CD₃OD) δ 7.87 (s, 1H), 7.71-7.56 (m, 4H), 5.48 (s,
	1H), 4.33 (d, J = 11.9 Hz, 2H), 4.06-3.85 (m, 3H), 3.85-3.53 (m, 5H),
	3.52-3.30 (m, 2H), 2.85 (s, 3H), 2.05-1.63 (m, 4H).
267	¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 8.8
	Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 5.51 (s, 1H), 4.79 (d, J = 2.9 Hz, 1H),
	4.33 (dd, J = 1.7, 12.0 Hz, 1H), 4.18 (br d, J = 7.8 Hz, 1H), 4.05-3.90 (m,
	3H), 3.76 (dt, J = 3.2, 11.4 Hz, 1H), 3.48-3.23 (m, 4H), 2.98 (s, 3H), 2.11
	(d, J = 10.3 Hz, 2H), 1.89 (br d, J = 12.7 Hz, 2H), 1.59-1.49 (m, 1H),
	1.33-1.19 (m, 3H), 1.12 (m, 2H).
268	m/z 485 (M + H)
273	m/z 484 (M + H)
274	m/z 450 (M + H)
276	m/z 423 (M + H)
279	m/z 406 (M + H)
280	¹H NMR (400 MHz, CDCl₃): δ 7.97 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.32
	(d, J = 8.8 Hz, 4H), 7.26-7.21 (m, 2H), 5.99 (d, J = 9.3 Hz, 1H), 5.33 (br
	s, 2H), 4.99 (m, 1H), 4.69-4.56 (m, 2H), 4.38-4.20 (m, 2H), 3.57 (s, 2H),
	3.22 (dd, J = 9.5, 18.3 Hz, 1H), 2.62-2.57 (m, 1H).
282	m/z 429 (M + H)
283	m/z 428 (M + H)
284	m/z 428 (M + H)
285	¹H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 1.7 Hz, 1H), 7.55-7.47 (m,
	2H), 7.17 (dq, J = 8.9, 1.0 Hz, 2H), 5.51 (d, J = 2.8 Hz, 1H), 4.87 (s, 1H),
	4.54 (d, J = 8.0 Hz, 1H), 4.33 (dd, J = 12.1, 2.1 Hz, 1H), 4.04-3.91 (m,
	3H), 3.89-3.64 (m, 3H), 3.49-3.26 (m, 4H), 2.19-2.06 (m, 2H), 1.97-1.84
	(m, 2H), 1.65-1.45 (m, 1H), 1.38-1.20 (m, 2H), 1.20-1.01 (m, 2H).
286	¹H NMR (300 MHz, CD₃OD) δ 7.86 (d, J = 1.6 Hz, 1H), 7.66-7.60 (m,
	4H), 5.44 (t, J = 3.1 Hz, 1H), 4.31 (dd, J = 12.1, 2.9 Hz, 1H), 4.06-3.74
	(m, 7H), 3.61 (d, J = 2.0 Hz, 2H), 3.53-3.39 (m, 3H), 2.67 (s, 3H), 2.14-1.99
	(m, 2H), 1.72-1.54 (m, 2H).
287	¹H NMR (300 MHz, DMSO-d₆) δ 7.84 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 8.2
	Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.12 (s, 1H), 5.44-5.39 (m, 1H), 4.27
	(dd, J = 12.1, 2.5 Hz, 1H), 3.89 (m, 3H), 3.72-3.60 (m, 1H), 3.41-3.25
	(m, 2H), 3.20-3.12 (m, 2H), 2.41 (d, J = 6.5 Hz, 2H), 1.80-1.67 (m, 4H),
	1.60-1.43 (m, 2H), 1.07-0.80 (m, 4H).
288	¹H NMR (300 MHz, DMSO-d₆) δ 7.83 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 8.2
	Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.15-7.06 (m, 1H), 5.41 (s, 1H), 4.27
	(dd, J = 12.1, 2.5 Hz, 1H), 3.99-3.80 (m, 3H), 3.71-3.60 (m, 1H), 3.39-3.25
	(m, 2H), 3.18-3.11 (m, 2H), 2.75 (d, J = 6.7 Hz, 2H), 1.75-1.57 (m,
	5H), 1.57-1.41 (m, 1H), 1.03-0.79 (m, 4H).
290	¹H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H),
	7.32 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 3.9 Hz, 1H), 6.54 (d, J = 2.9 Hz, 1H),
	5.93 (s, 1H), 4.53 (d, J = 13.2 Hz, 1H), 4.42 (d, J = 11.7 Hz, 1H), 4.14-4.05
	(m, 2H), 4.00-3.91 (m, 2H), 3.66 (dt, J = 2.7, 11.6 Hz, 1H), 3.57-3.43
	(m, 3H), 2.81 (s, 3H), 2.69-2.55 (m, 2H), 1.97 (m, 1H), 1.54 (br d, J =
	11.2 Hz, 2H), 1.32-1.19 (m, 2H).
291	¹H NMR (400 MHz, CDCl₃): δ 7.95 (s, 1H), 7.56 (s, 4H), 7.19 (d, J = 8.3
	Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 5.53 (s, 1H), 5.15-5.06 (m, 1H), 4.58 (d,
	J = 5.4 Hz, 2H), 4.32 (d, J = 12.2 Hz, 1H), 4.03-3.86 (m, 3H), 3.80-3.70
	(m, 1H), 3.40 (t, J = 10.5 Hz, 1H), 2.60 (s, 1H).
292	¹H NMR (300 MHz, CD₃OD) δ 7.85 (d, J = 1.6 Hz, 1H), 7.67-7.62 (m,
	4H), 7.32 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 5.51-5.44 (m, 1H),
	4.62 (s, 2H), 4.33 (dd, J = 12.1, 2.8 Hz, 1H), 4.07-3.89 (m, 3H), 3.85-3.75
	(m, 1H), 3.66 (s, 2H), 3.53-3.37 (m, 1H).
293	¹H NMR (400 MHz, CDCl₃): δ 8.72 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.92
	(m, 2H), 7.60 (s, 4H), 5.60 (s, 1H), 5.22 (s, 1H), 4.81 (d, J = 5.9 Hz,
	2H), 4.38 (dd, J = 2.0, 12.2 Hz, 1H), 4.09-3.99 (m, 2H), 3.95 (d, J = 11.2
	Hz, 1H), 3.78 (dt, J = 2.7, 11.4 Hz, 1H), 3.44 (ddd, J = 3.4, 11.0, 13.9 Hz,
	1H), 3.22 (s, 3H).
294	m/z 505 (M + H)
295	m/z 469 (M + H)
296	m/z 427 (M + H)
297	m/z 504 (M + H)
299	m/z 450 (M + H)
300	m/z 422 (M + H)
301	m/z 450 (M + H)
302	m/z 420 (M + H)
303	m/z 448 (M + H)
304	m/z 436 (M + H)
305	m/z 485 (M + H)
306	m/z 440 (M + H)
307	m/z 460 (M + H)
308	m/z 488 (M + H)
309	m/z 520 (M + H)
310	m/z 463 (M + H)
311	m/z 456 (M + H)
312	m/z 456 (M + H)
313	m/z 410 (M + H)
314	m/z 412 (M + H)
315	m/z 412 (M + H)
316	m/z 424 (M + H)
317	m/z 424 (M + H)
318	m/z 466 (M + H)
319	m/z 497 (M + H)
320	m/z 554 (M + H)
323	m/z 490 (M + H)
324	m/z 518 (M + H)
325	m/z 455 (M + H)
326	¹H NMR (300 MHz, CDCl₃): δ 8.92 (s, 1H), 8.40 (s, 1H), 8.09 (d, J = 8.4
	Hz, 1H), 7.69-7.60 (m, 1H), 7.25-7.17 (m, 4H), 6.95 (d, J = 3.7 Hz, 1H),
	6.42 (d, J = 3.7 Hz, 1H), 6.21 (s, 1H), 5.40 (s, 2H), 5.33 (br s, 2H), 4.49 (d,
	J = 12.5 Hz, 1H), 4.39 (d, J = 12.8 Hz, 1H), 4.18-4.05 (m, 2H), 3.90-3.76
	(m, 1H), 3.68-3.58 (m, 1H), 3.56 (s, 2H).
327	m/z 504 (M + H)
328	¹H NMR (300 MHz, CDCl₃): δ 8.91 (s, 1H), 8.38 (s, 1H), 7.84 (d, J = 8.4
	Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25-7.16 (m, 4H), 6.91 (d, J = 3.7 Hz,
	1H), 6.35 (d, J = 3.7 Hz, 1H), 5.96 (s, 1H), 5.47-5.29 (m, 4H), 4.93 (d, J =
	11.3 Hz, 1H), 4.70 (d, J = 12.4 Hz, 1H), 4.04 (dd, J = 3.7, 11.3 Hz, 2H),
	3.88-3.62 (m, 2H), 3.55 (s, 2H).
329	m/z 534 (M + H)
330	m/z 534 (M + H)

Biological Evaluation
The activity of the compounds was evaluated using a Fluorescence Polarization (FP) Assay and, in most cases, a Th17 Assay and/or RORγ Reporter assay (also referred to as Gal4 assay). The FP assay is an in vitro assay monitoring binding within the ligand binding pocket. The RORγ and the Th17 assays are both cell-based assays monitoring functional activity of the compound assayed.
Fluorescence Polarization (FP) Assay
A buffer containing 10 mM Hepes, 150 mM NaCl, 1 mM DTT, 0.05% Pluronic F-127 detergent (all from Sigma), and 100 nM human RORγt (Ligand Binding Domain obtained from Crelux (Planegg, Germany), batch no PC5032-1) was complemented with 1 μl test compounds diluted in 100% DMSO. The total volume was 25 μl, in a black Perkin Elmer OptiPlate. As negative control, 1 μl DMSO was used. Samples were incubated at room temperature for 30 min, followed by addition 5 μl of probe diluted in assay buffer to a concentration of 125 nM (final concentration of probe is 25 nM). The probe is a fluorescently labeled (TAMRA) RORγt ligand identified by Nuevolution with a total molecular weight of 910 g/mole as shown in Graph A in FIG. 1. Graph (B) in FIG. 2 shows the polarization signal rises with increasing concentration of human RORγt (LBD), using 50 nM TAMRA-labelled probe concentration. Graph (C) of FIG. 2 shows the RORγt inhibitor SR2211 (1,1,1,3,3,3-hexafluoro-2-(2-fluoro-4′-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; see Kumar et al, ACS Chem. Biol., 2012, 7 (4), pp 672-677) inhibits the probe from binding RORγt with an IC50 of 0.36 μM, which is close to the value reported in the literature. The plate was incubated for 10 min at room temperature and fluorescence polarization was read using an Envision 2102 plate reader (Perkin Elmer) with the TAMRA FP optical module installed.
Th17 Assay
Human peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats of healthy human volunteers using the Ficoll paque PLUS kit (GE Healthcare, cat no 17-1440-02), as instructed by the manufacturer. Naive CD4+ T cells were isolated with Naive CD4+ T cell kit, human (Milteny Biotec, cat no 130-094-131). The following modifications were made to the manufacturer's protocol: 1) Incubation with Biotin-Antibody Cocktail and Anti-Biotin MicroBeads was prolonged to 30 minutes, and 2) Cells were washed with 40 mL of Miltenyi buffer. Differentiation of Th17 cells in anti-CD3 (BD Pharmingen, 5 μg/ml) coated 96-well plates (400,000 cells/well, 160 μl RPMI 1640+10% Fetal Bovine Serum) containing 5 μg/ml anti-CD28 (BD Pharmingen), 10 ng/ml IL-2 (R&D Systems), 2.5 ng/ml TGFβ-1 (R&D Systems), 20 ng/ml IL-1β (R&D Systems), 20 ng/ml IL-6 (R&D Systems), 30 ng/ml IL-23 (R&D Systems), 2.5 μg/ml anti-IL-4 (R&D Systems) and 1 μg/ml anti-IFNγ (R&D Systems) and with test compound during the entire differentiation (or vehicle, 0.1% DMSO for control). Test compounds were tested in triplicates, diluted 1000-fold in medium (final DMSO concentration is 0.1%). Incubated for seven days at 37° C., 5% CO₂, 95% humidity, and 2-fluoro-4′-[[4-(4-pyridinylmethyl)-1-piperazinyl]methyl]-α,α-bis(trifluoromethyl)-[1,1′-biphenyl]-4-methanol (SR2211 Calbiochem, Cat. No. 557353) was used as positive control. As negative control, cells were differentiated into Th0 using 5 μg/ml anti-CD28 (BD Pharmingen), 10 ng/ml IL-2 (R&D Systems), 2 μg/ml anti-IL4 (R&D Systems) and 2 μg/ml anti-IFNγ (R&D Systems) are negative control. IL-17 levels in supernatants were measured with ELISA (R&D Systems).
RORγ Reporter Assay (Gal4)
Cell-based RORγ functional assays were performed using a commercially available assay product (INDIGO Biosciences, State College, Pa., USA; product #IB04001). The RORγ reporter cells are HEK293t cells transfected with one vector that provides high level constitutive expression of a hybrid protein comprised of the yeast Gal4-DNA binding domain fused to the ligand binding domain of human RORγ, and a second vector comprising the firefly luciferase cDNA functionally linked to the upstream activation sequence (UAS) of yeast Gal4. A suspension of RORγ Reporter Cells was prepared using the protocol and culture medium provided in the kit product, and 100 μl of the Reporter Cell suspension was then dispensed into wells of a white, collagen-treated, 96-well assay plate. Concentrated stocks of test compounds were prepared in DMSO, then further diluted using media provided in the kit to generate ‘2×-concentration’ treatment media. 100 μl of medium for each respective treatment concentration dispensed into triplicate assay wells, thereby combining with the reporter cells. All media formulations contained 10% charcoal stripped Fetal Bovine Serum, but are otherwise proprietary to INDIGO Biosciences. Final treatment concentrations for each test compound were 1,000 nM and 100 nM, each with 0.1% residual DMSO. Separate control treatments were media supplemented with vehicle only (0.1% DMSO) to determine the constitutive level of RORγ activity in the reporter cells, and the reference inverse-agonist ursolic acid (f.c. 6,000 nM to 8.2 nM in 3-fold decrements) to establish a positive control inverse-agonist dose response. Assay plates were placed in a 37° C., 5% CO₂, 85% humidity incubator for 24 hour. Treatment media were then discarded, 100 μl of luciferase detection reagent was added to each well, and relative light units (RLUs) were quantified from each assay well using a plate reading luminometer. Values of average RLU+/−standard deviation were computed for all treatment sets, followed by the calculations of fold-reduction: [Average RLU_Vehicle/Average RLU_{Test Cmpd}]. Percent-reduction of RORγ activity in response to respective test compound treatments was calculated: [100*(1−[Ave RLU_{Test Cmpd}/Ave RLU_Vehicle)] where the theoretical minimum reduction (0% reduction) derives from Vehicle treatment only, no treatment compound.
In some aspects it may be of interest to provide compounds with selective modulation of RORγ for example compounds that are selective to RORγ over RORα, compounds that are selective for RORγ versus RORβ, and compounds that are selective for RORγ versus BOTH RORα and RORβ. It may also be of interest to provide compounds that are selective for RORγ versus further nuclear hormone receptors such as CAR1, FXR, GR, LXRα, LXRβ, PPARα, PXR, RARα, RXRα, TRα, VDR. It is apparent to those skilled in the art that these nuclear hormone receptors are merely examples, and that selectivity against other nuclear receptors may also be of interest. It may for example be of interest to provide compounds that modulate RORγ and one or more further nuclear hormone receptors, as well as compounds that modulate both RORγ and RORα, or RORγ and RORP. It may also be of interest to provide compounds that modulate RORγ and BOTH RORα and RORβ, as well as compounds that modulate both RORγ and one or more further nuclear hormone receptors such as CAR1, FXR, GR, LXRα, LXRβ, PPARα, PXR, RARα, RXRα, TRα, VDR. It is apparent to those skilled in the art that these nuclear hormone receptors are merely examples, and that modulation of even other nuclear receptors may also be of interest. By substituting the ligand binding domain of another nuclear hormone receptor for the ligand binding domain of RORγ, the reporter assay (Gal4) may be modified to provide activity data for compounds against said other nuclear hormone receptor. Those skilled in the art know how to accomplish such modification. By comparing activity against RORγ to activity against another nuclear hormone receptor in this assay, the selectivity of a compound towards RORγ versus said other nuclear hormone receptor can be established. A compound may be said to be selective for RORγ versus another nuclear hormone receptor if the activity of the compound against RORγ is greater than 5, 10, 20, or 100 fold higher for RORγ than for said other nuclear receptor. The compound(s) or pharmaceutical composition(s) described herein may modulate the activity of an RORγ receptor to a larger extent than it modulates the activity of RORα and/or RORβ receptors.
The results of the Fluorescence Polarization (FP) Assay, Th17 Assay, and RORγ Reporter (Gal4) Assay are shown in Tables 2-5 below.

TABLE 2

Activity Data of Example Compounds obtained from
the Fluorescence Polarization (FP) Assay.

	Example.	FP activity range
	No.	(nM)

	4	<500
	5	<500
	6	<10000
	9	<500
	11	<500
	13	<10000
	14	<10000
	15	<10000
	17	<500
	18	<500
	19	<500
	20	<2000
	21	<10000
	23	<500
	24	<500
	26	<500
	29	<1000
	30	<500
	31	<10000
	32	<500
	33	<10000
	34	<1000
	35	<500
	36	<2000
	37	<1000
	38	<2000
	39	<10000
	40	<1000
	41	<2000
	42	<2000
	43	<1000
	44	<10000
	45	<10000
	46	<1000
	48	<2000
	51	<1000
	52	<2000
	53	<1000
	54	<1000
	55	<10000
	56	<2000
	57	<10000
	58	<10000
	59	<10000
	60	<2000
	61	<10000
	62	<500
	63	<2000
	64	<2000
	65	<500
	66	<2000
	67	<2000
	68	<2000
	69	<1000
	70	<2000
	71	<10000
	72	<1000
	73	<2000
	74	<2000
	79	<500
	81	<500
	85	<500
	88	<500
	89	<500
	90	<1000
	91	<500
	93	<500
	94	<500
	95	<1000
	97	<1000
	98	<1000
	100	<2000
	105	<10000
	106	<10000
	107	<10000
	108	<10000
	109	<2000
	110	<10000
	111	<500
	113	<500
	114	<1000
	115	<500
	116	<1000
	117	<500
	118	<10000
	119	<1000
	120	<10000
	122	<10000
	123	<10000
	126	<2000
	128	<500
	129	<500
	130	<10000
	131	<2000
	132	<10000
	134	<10000
	135	<10000
	136	<2000
	137	<10000
	138	<500
	139	<2000
	140	<500
	141	<2000
	142	<2000
	143	<2000
	144	<10000
	145	<10000
	146	<2000
	147	<2000
	148	<1000
	150	<10000
	151	<10000
	152	<500
	154	<500
	155	<10000
	159	<2000
	161	<500
	164	<500
	165	<500
	166	<500
	167	<500
	168	<500
	169	<500
	170	<10000
	175	<10000
	178	<500
	181	<10000
	182	<500
	183	<500
	184	<500
	185	<1000
	186	<500
	188	<500
	189	<500
	190	<500
	191	<500
	192	<500
	193	<10000
	194	<2000
	195	<500
	196	<500
	197	<500
	198	<500
	199	<1000
	200	<1000
	201	<500
	202	<10000
	203	<2000
	204	<500
	205	<500
	206	<1000
	207	<500
	208	<500
	209	<1000
	210	<1000
	211	<1000
	212	<10000
	213	<10000
	214	<10000
	215	<10000
	216	<10000
	217	<10000
	218	<10000
	219	<10000
	220	<500
	221	<500
	222	<2000
	223	<500
	224	<500
	225	<500
	226	<10000
	227	<500
	228	<500
	229	<500
	230	<500
	231	<500
	232	<500
	233	<500
	234	<1000
	235	<2000
	236	<500
	237	<500
	238	<10000
	239	<500
	240	<500
	241	<1000
	242	<2000
	243	<500
	244	<2000
	245	<1000
	246	<500
	247	<10000
	248	<1000
	249	<10000
	250	<10000
	251	<10000
	252	<500
	253	<1000
	254	<500
	255	<2000
	256	<10000
	257	<500
	258	<500
	259	<500
	260	<500
	261	<1000
	262	<1000
	263	<500
	264	<500
	265	<500
	266	<500
	267	<500
	268	<10000
	273	<500
	274	<2000
	276	<2000
	278	<500
	280	<500
	282	<10000
	283	<1000
	284	<500
	285	<500
	286	<2000
	287	<500
	288	<500
	290	<500
	291	<1000
	292	<500
	293	<1000
	294	<10000
	295	<500
	296	<10000
	297	<10000
	299	<1000
	300	<10000
	301	<500
	302	<500
	303	<500
	304	<500
	305	<500
	306	<500
	307	<2000
	308	<10000
	309	<2000
	310	<500
	311	<500
	312	<500
	313	<500
	314	<10000
	315	<10000
	316	<500
	317	<10000
	318	<500
	319	<500
	320	<500
	323	<500
	324	<500
	325	<1000
	326	<500
	327	<1000
	328	<500
	329	<2000
	330	<2000

TABLE 3

Activity Data of Example Compounds
obtained from the Th17 Assay.

	Example.	Th17 activity range @ 1 μM
	No.	(% inhibition)

	6	>20
	13	>20
	16	>0
	18	>80
	19	>80
	29	>50
	30	>50
	33	>20
	35	>50
	36	>50
	38	>50
	40	>80
	62	>80
	67	>80
	77	>50
	78	>50
	79	>50
	80	>50
	81	>80
	83	>20
	85	>80
	88	>80
	89	>20
	91	>80
	94	>80

TABLE 4

Activity Data of Example Compounds obtained from the
RORγ Reporter Assay (Gal4) at 1 μM.

	Example.	Gal4 activity range @ 1 μM
	No.	(% inhibition)

	14	>0
	17	>80
	20	>50
	30	>80
	31	>0
	39	>20
	42	>20
	43	>80
	51	>80
	52	>80
	53	>20
	54	>50
	56	>20
	60	>20
	62	>80
	63	>20
	64	>20
	65	>20
	66	>50
	67	>80
	68	>80
	69	>50
	72	>80
	73	>20
	74	>80
	79	>50
	81	>80
	84	>20
	85	>80
	86	>20
	87	>20
	89	>80
	90	>20
	91	>80
	93	>50
	94	>80
	95	>80
	96	>20
	97	>80
	98	>80
	99	>50
	100	>20
	104	>20
	106	>20
	107	>0
	109	>20
	110	>0
	111	>80
	112	>20
	113	>80
	114	>80
	115	>80
	116	>50
	117	>80
	118	>20
	119	>80
	121	>50
	123	>20
	124	>20
	126	>50
	190	>80
	191	>80
	197	>80
	198	>80
	199	>80
	200	>80
	201	>80
	202	>50
	203	>50
	204	>80
	205	>80
	206	>80
	207	>80
	208	>80
	209	>50
	210	>80
	211	>50
	220	>80
	221	>80
	222	>80
	223	>80
	224	>80
	225	>80
	226	>50
	227	>80
	228	>80
	229	>80
	230	>80
	231	>80
	232	>80
	233	>80
	234	>50
	235	>50
	236	>80
	237	>80
	238	>50
	239	>80
	240	>80
	245	>80
	246	>80
	247	>80
	248	>80
	252	>80
	253	>80
	254	>80
	255	>50
	257	>80
	258	>80
	259	>80
	260	>80
	261	>80
	262	>50
	263	>80
	264	>80
	265	>80
	266	>80
	267	>80
	273	>80
	274	>50
	276	>20
	279	>50
	280	>20
	282	>0
	283	>20
	284	>50
	285	>20
	286	>20
	287	>80
	288	>80
	290	>80
	291	>50
	292	>20
	295	>80
	299	>80
	300	>20
	301	>80
	302	>50
	303	>80
	304	>80
	305	>80
	306	>80
	307	>50
	308	>50
	313	>80
	316	>80
	318	>20
	319	>0
	320	>80
	323	>80
	324	>80
	326	>80
	327	>80
	328	>80

TABLE 5

Activity Data of Example Compounds obtained from the
RORγ Reporter Assay (Gal4) at 0.1 μM.

	Example.	Gal4 activity range @ 0.1 μM
	No.	(% inhibition)

	73	>0
	89	>20
	90	>0
	91	>20
	93	>0
	94	>80
	95	>20
	96	>0
	97	>20
	98	>20
	99	>20
	104	>0
	111	>50
	112	>0
	113	>50
	114	>20
	115	>50
	116	>20
	117	>50
	118	>0
	119	>20
	121	>20
	123	>0
	126	>20
	128	>50
	129	>50
	131	>20
	140	>20
	148	>50
	152	>0
	161	>20
	164	>20
	165	>50
	167	>0
	168	>50
	169	>0
	182	>50
	183	>50
	185	>50
	186	>0
	188	>0
	189	>20
	190	>80
	191	>50
	192	>50
	195	>80
	196	>80
	197	>80
	198	>20
	199	>20
	200	>20
	201	>0
	202	>0
	203	>0
	204	>50
	205	>50
	206	>20
	207	>20
	208	>50
	209	>20
	210	>50
	211	>0
	220	>20
	221	>50
	222	>20
	223	>50
	224	>80
	225	>80
	227	>80
	228	>20
	229	>50
	230	>50
	231	>50
	232	>50
	233	>20
	234	>0
	235	>0
	236	>80
	237	>80
	238	>0
	239	>20
	240	>80
	245	>20
	246	>20
	247	>20
	248	>20
	252	>80
	253	>50
	254	>50
	255	>20
	257	>50
	258	>80
	259	>50
	260	>50
	261	>20
	262	>20
	263	>50
	264	>20
	265	>80
	266	>80
	267	>80
	273	>20
	274	>20
	276	>0
	279	>20
	280	>0
	282	>0
	283	>0
	284	>20
	285	>0
	286	>20
	287	>50
	288	>80
	290	>50
	291	>0
	292	>0
	295	>20
	299	>0
	300	>20
	301	>50
	302	>20
	303	>80
	304	>20
	305	>50
	306	>50
	307	>20
	308	>20
	313	>20
	316	>20
	318	>20
	320	>80
	323	>80
	324	>50
	326	>50
	327	>20
	328	>80

As can be seen from the tables above, the compounds were found to show beneficial activity across the assays. FIG. 3 graphically illustrates the assay results of example no. 89.
According to an embodiment, compounds having inhibition values of greater than 80% in both an RORγ Reporter Assay (Gal4) and a Th17 Assay are disclosed herein. According to an embodiment the compounds have inhibition values of greater than 80% in both a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 1000 nM, such as less than 500 nM.
According to an embodiment the compounds are having inhibition values of greater than 80% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 80% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 1000 nM, such as less than 500 nM.
According to an embodiment the compounds are having inhibition values of greater than 50% in both an RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 50% in both a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 1000 nM, such as less than 500 nM.
According to an embodiment the compounds are having inhibition values of greater than 50% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 50% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.
According to an embodiment the compounds are having inhibition values of greater than 20% in both an RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 20% in both a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.
According to an embodiment the compounds are having inhibition values of greater than 50% in a RORγ Reporter Assay (Gal4) at 1 μM and inhibition values of greater than 20% in a RORγ Reporter Assay (Gal4) at 0.1 μM. According to an embodiment the compounds are having inhibition values of greater than 50% in a RORγ Reporter Assay (Gal4) at 1 μM and inhibition values of greater than 20% in a RORγ Reporter Assay (Gal4) at 0.1 μM, and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.
According to an embodiment the compounds are having inhibition values of greater than 20% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 20% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.
Experimental Autoimmune Encephalomyelitis (EAE) Study
EAE is an animal model for multiple sclerosis used to evaluate the efficacy of test compounds. EAE was induced at WuXi AppTec (Shanghai) in female C57BL/6 mice obtained from SLAC Laboratories, Shanghai by injection of 100 μl (100 μg MOG_35-55peptide in complete Freund's adjuvant containing 200 μg M. tuberculosis/mouse) emulsion (with a 25-G needle) subcutaneously in the shaved back of the mouse. Each mouse was also given 200 ng PTX in 200 μl of PBS by intraperitoneal injection at 0 and 48 hours after immunization. For treatment, compound or vehicle (2% DMSO, 10% HP-β-CD in MilliQ water) was given orally twice daily at various doses selected from 3, 10, and 30 mg/kg, beginning at the day of EAE induction. Treatment lasted for 25 days, and the animals were scored daily for EAE symptoms using the following scoring system: 0, Normal mouse; no overt signs of disease; 1, Limp tail or hind limb weakness but not both; 2 Limp tail and hind limb weakness; 3 Partial hind limb paralysis; 4 Complete hind limb paralysis; 5 Moribund state; death by EAE: sacrifice for humane reasons. The clinical score can be expressed as the mean score for each treatment group+/−S.E.M.
Results: Example 204 was tested in the EAE study at 10 and 30 mg/kg. Example 204 was shown to delay onset and lower clinical score at both doses.
Collagen-Induced Arthritis (CIA) Study
Collagen-induced arthritis is an animal model of rheumatoid arthritis used to evaluate the efficacy of test compounds. CIA was induced at Washington Biotechnology Inc. (Baltimore) in male DBA/1J mice (Jackson Laboratories) by subcutaneous injection at the base of the tail with 50 μl of a bovine collagen/complete Freund's adjuvant emulsion. After 21 days, the mice were further boosted by a further subcutaneous injection of 50 μl of a collagen/incomplete Freund's adjuvant emulsion. For treatment, compound or vehicle (2% DMSO, 10% HP-β-CD in MilliQ water) was given orally twice daily at various doses selected from 3, 10, 30 mg/kg, beginning at the day of CIA induction (Prophylactic setting), or after disease initiation (at day 27, therapeutic setting). Treatment lasted until day 41, and the animals were scored three times weekly. Each paw was scored and the sum of all four scores was recorded as the Arthritic Index (AI). The maximum possible AI was 16. 0=no visible effects of arthritis; 1=edema and/or erythema of one digit; 2=edema and/or erythema of 2 joints; 3=edema and/or erythema of more than 2 joints; 4=severe arthritis of the entire paw and digits including limb deformation and ankylosis of the joint. The Arthritis Index for each treatment can be expressed as the mean score for each treatment group+/−S.E.M.
Results: Example 204 was tested in the CIA study at 10 and 30 mg/kg in prophylactic setting and at 30 mg/kg in therapeutic setting. Example 204 was shown to significantly reduce disease severity at both prophylactic doses. Example 204 was shown to arrest disease development in the therapeutic setting.
In summary, compounds disclosed herein have been found to at least modulate the activity of RORγ. Additionally it has been found that compounds disclosed herein have in vivo usefulness, and could consequently be useful in treating inflammatory, metabolic and autoimmune diseases.

Claims

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Y is NR or O;

R is hydrogen or substituted or unsubstituted C_1-4alkyl;

R₁is selected from the group consisting of hydrogen, —OH, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, and substituted or unsubstituted C_2-4alkenyl;

R₂is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, —CN, and —OH;

or R and R₂are combined to form a substituted or unsubstituted fused ring;

R₃is selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, oxo, and —C(═O)R₁₀;

R_4ais selected from the group consisting of hydrogen, halogen, —OH, —CN, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C_1-6alkyl;

R_4bis selected from the group consisting of hydrogen, halogen, oxo, —OH, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, and —C(═O)R₁₀;

R₅is selected from the group consisting of —(CR₈R₉)pOR₁₂, —(CR₈R₉)p-CR₁₃R₁₄R₁₅, —(CR₈R₉)p-C(═O)OR₇, and —(CR₈R₉)p-C(═O)NR₈R₉;

n, m, and p are integers independently selected from the group consisting of 0, 1, 2, 3 and 4;

R_6aand R_6bare independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_2-6alkynyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_1-6heteroalkyl, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or

R_6aand R_6btaken together form an oxo group or

R_6aand R_6btaken together with the carbon to which they are attached form a ring system selected from the group consisting of substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl, or R_6aand R₁₃are taken together to form a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-5heteroalicyclyl;

R₇, R₈, R₉, and R₁₂, are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_3-6cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted C_2-9heteroalicyclyl;

R₁₀is selected from the group consisting of substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, —OH, —NH₂, —NH(C_1-6alkyl), —N(C_1-6alkyl)₂, and substituted or unsubstituted C_3-7cycloalkyl;

R₁₃is absent, or selected from the group consisting of hydrogen, —OH, —CN, fluorine, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, and —(CR₈R₉)p-C(═O)OR₇, —(CR₈R₉)p-SO₂R₇and —(CR₈R₉)p-C(═O)NR₈R₉;

R₁₄and R₁₅are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl; or

R₁₄and R₁₅taken together with the carbon to which they are attached form a ring system selected from the group consisting of substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, substituted or unsubstituted C_2-9heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic heteroalicyclyl, provided that B is not 5,6-dichloro-1H-benzo[d]imidazol-2-yl when R₁and R₂are both hydrogen;

C is a C_2-9heteroalicyclyl ring system; and wherein

B is attached to a carbon atom adjacent the N atom of ring system C; with the proviso the compound of Formula I is not:

2. The compound of claim 1, wherein R and R₂together with the pyrimidine ring of formula (I) form a pyrrolo[2,3-d]pyrimidine or 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine.

3. The compound of claim 1, having the Formula (IIa):

wherein:

R_4eand R_4dare independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4alkoxy, and —OH.

4. The compound of claim 3, wherein R_4eand R_4dare independently selected from the group consisting of hydrogen, methyl, and fluorine.

5. The compound of claim 1, wherein R₅is —(CR₈R₉)p-C(═O)OR₇, or —(CR₈R₉)p-C(═O)NR₈R₉.

6. The compound of claim 1, wherein R₅is —(CR₈R₉)pOR₁₂.

7. The compound of claim 1, wherein R₅is —(CR₈R₉)p-CR₁₃R₁₄R₁₅.

8. The compound of claim 7, wherein R₁₄and R₁₅taken together with the carbon to which they are attached form a ring system selected from the group consisting of substituted or unsubstituted C_3-7cycloalkyl, substituted or unsubstituted C_3-7cycloalkenyl, substituted or unsubstituted C_2-6heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

9. The compound of claim 7, wherein R₁₄and R₁₅taken together with the carbon to which they are attached form a ring system selected from the group consisting of substituted or unsubstituted C_4-7cycloalkyl, substituted or unsubstituted C_6-12aryl, substituted or unsubstituted 4-membered heteroalicyclyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 5-membered heteroalicyclyl, substituted or unsubstituted 6-membered heteroaryl, a substituted or unsubstituted 6membered heteroalicyclyl, substituted or unsubstituted 7-membered heteroaryl, and a substituted or unsubstituted 7-membered heteroalicyclyl.

10. The compound of claim 7, wherein R₁₄and R₁₅taken together with the carbon to which they are attached form a ring system selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, thietanyl, pyrrolyl, pyrazolyl imidazolyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathianyl thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolanyl, dioxanyl, furyl, dihydrofuranyl, furazanyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dithianyl, thiopyranyl, thianyl, thienyl, oxetanyl, quinolyl, isoquinolyl, indolyl, iso-indolyl, and tetrahydrothienyl, any of which may be substituted or unsubstituted.

11. The compound of claim 10, wherein the ring system is selected from the group consisting of cycloheptyl, cyclohexyl, cyclopentyl, dioxanyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxathianyl, phenyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, tetrazolyl, thianyl, thiazolyl, thienyl, thiomorpholinyl, thiopyryl, and triazolyl, any of which may be substituted or unsubstituted.

12. The compound of claim 8, wherein the ring system is substituted with —(CH₂)q(R_5a) wherein R_5ais independently selected from the group consisting of —CH₂COOR₂₀, —CH₂CONR₂₁R₂₂, oxo, —CN, CH₂CN, C_1-6alkyl, —CH₂-imidazolyl, —CH₂—SO₂R₂₀, CH₂C(CH₃)₂(OR₂₀), —OR₂₀, —CH₂-triazolyl, —CF₃, dimethyl substituted-imidazolyl-2,4-dione, —CH₂—SO₂NR₂₁R₂₂, morpholinyl, —C(═O)-morpholinyl, piperidyl-CH₂₀R₂₀, OCH₂-tetrahydrofuryl, piperazinonyl, piperidinyl-CONR₂₁R₂₂, —OH, —CONR₂₁R₂₂, CH(OR₂₀)CH₃, —COOR₂₀, —CH₂-pyrrolidyl, C_1-6alkylene-OH, cyclopentyl, pyrrolidonyl, —NR₂₁SO₂R₂₀, tetrazolyl, —CH₂-tetrazolyl, —CH₂₀R₂₀, acyl, —SOR₂₀, —SO₃R₂₀, —SO₂R₂₀, —SO₂NR₂₁R₂₂, and halogen;

R₂₀, R₂₁, and R₂₂are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, —CN, substituted or unsubstituted C_3-6cycloalkyl, substituted or unsubstituted C_2-6heteroalicyclyl; and

q is an integer selected from 0, 1 or 2.

13. The compound of claim 7, wherein R₁₃is absent or selected from the group consisting of hydrogen, —CN, —CH₃, fluorine, —OH, —CH₂₀H, —OCH₃, —CH₂CH₂OH, —CO₂H, —CO₂—C_1-4-alkyl, and —CONR₈R₉; wherein R₈and R₉are independently selected from the group consisting of hydrogen, C_1-4alkyl, and C_1-4aminoalkyl, or R₈and R₉taken together with the nitrogen to which they are attached form a C₂-C₆heteroalicyclyl.

14. The compound of claim 1, wherein Y is NR.

15. The compound of claim 14, wherein R is selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, and C_1-4hydroxyalkyl.

16. The compound of claim 15, wherein R is hydrogen.

17. The compound of claim 16, wherein R₁is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-4alkyl, and substituted or unsubstituted C_1-4alkoxy.

18. The compound of claim 17, wherein R₁is selected from the group consisting of hydrogen, halogen, C_1-4alkyl, C_1-4haloalkyl, and C_1-4hydroxyalkyl.

19. The compound of claim 18, wherein R₁is hydrogen or —CF₃.

20. The compound of claim 19, wherein R₂is selected from the group consisting of hydrogen, halogen, C_1-4alkyl, C_1-4haloalkyl, and C_1-4hydroxyalkyl.

21. The compound of claim 20, wherein R₂is halogen.

22. The compound of claim 21, wherein R₂is fluorine.

23. The compound of claim 1, wherein R₃is selected from the group consisting of hydrogen, halogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, oxo, C_1-4alkoxy and C_1-4haloalkoxy.

24. The compound of claim 23, wherein R₃is selected from the group consisting of hydrogen, methyl, fluorine, chlorine, and oxo.

25. The compound of claim 1, wherein whenever m is an integer selected from 2, 3, or 4, at least two of the R₃groups present are bound to the same atom of ring system C.

26. The compound of claim 1, wherein R_4ais selected from the group consisting of hydrogen, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, —CN, C₁-C₆alkoxy, C_1-6haloalkoxy, C₃-C₅cycloalkyl, heteroaryl and aryl.

27. The compound of claim 26, wherein R_4ais selected from the group consisting of halogen, C_1-4alkyl, C_1-4haloalkyl, C₁-C₄alkoxy, C_1-4haloalkoxy, and heteroaryl.

28. The compound of claim 27, wherein R_4ais selected from the group consisting of methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, fluorine, methoxy, ethoxy, C_1-2haloalkyl, C_1-2haloalkoxy, and triazolyl.

29. The compound of claim 28, wherein R_4ais selected from the group consisting of —CF₃, —CHF₂, —OCF₃, and —OCHF₂.

30. The compound of claim 1, wherein R_4bis selected from the group consisting of hydrogen, oxo, halogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C₁-C₄alkoxy, and C_1-4haloalkoxy.

31. The compound of claim 1, wherein R_4bis selected from the group consisting of methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, fluorine, methoxy, ethoxy, —OH, C_1-2haloalkyl, and C_1-2haloalkoxy.

32. The compound of claim 1, wherein R_4bis selected from the group consisting of —CF₃, —CF₂CF₃, —CHF₂, —OCF₃, —OCF₂CF₃, and —OCHF₂.

33. The compound of claim 1, wherein R_4ais selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, and substituted or unsubstituted aryl; or

R_6aand R₁₃are combined to form a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl, or

R_6aand R_6btaken together with the carbon to which they are attached form a ring system selected from substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-9heteroalicyclyl.

34. The compound of claim 33, wherein R_6ais selected from the group consisting of hydrogen, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, and aryl.

35. The compound of claim 34, wherein R_6ais hydrogen.

36. The compound of claim 1, wherein R_6bis selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted C_2-9heteroalicyclyl-C_1-6alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl.

37. The compound of claim 1, wherein R_6bis selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C₁-C₆alkoxy, C_1-6haloalkoxy, C_1-6-alkoxy-C_1-6-alkyl; or

R_6bis selected from the group consisting of —(CH₂)_q—C_3-6cycloalkyl, —(CH₂)_q-aryl, —(CH₂)_q—C_2-9heteroalicyclyl, and —(CH₂)_q-heteroaryl, any of which can be unsubstituted or substituted by one or more substituent selected from the group consisting of halogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_3-5cycloalkyl, —(CH₂)_q—CONR₂₃R₂₄, —(CH₂)_q—SO₂R₂₃, —(CH₂)_q—NR₂₃SO₂R₂₄and —(CH₂)_q—SO₂NR₂₃, wherein

R₂₃, and R₂₄are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, —CN, substituted or unsubstituted C_3-6cycloalkyl, and substituted or unsubstituted C_2-6heteroalicyclyl; and

q is an integer selected from 0, or 1.

38. The compound of claim 37, wherein R_6bis selected from the group consisting of hydrogen, —(CH₂)C(CH₃)₃, —(CH₂)CONH₂, phenyl, phenyl substituted with 1 to 3 halogens, —CH(CH₃)OC(CH₃)₃, —CH₂-phenyl-OCH₃, phenyl-OCH₃, —CH₂-pyridyl, CH₂-cyclohexyl-CH₂CO₂H, —CH₂-cyclohexylCH₂CONH₂, CH₂-cyclohexyl-CH₂-tetrazolyl, —CH₂-cyclohexyl-CH₂OH, —CH₂cyclohexyl-NHSO₂CH₃, CH₂-cyclohexyl-NHSO₂CH₂CF₃, CH₂-cyclohexyl-CH₂CN, —CH₂-phenyl-CH₂CO₂H, —CH₂-phenyl-CH₂CONH₂, —CH₂-phenyl-CH₂CONH₂CH₃, —CH₂phenyl-CH₂-tetrazolyl, —CH₂-phenyl-CONH₂, —CH₂-phenyl-SO₂NH-cyclopropyl, —CH₂phenyl-SO₂CH₃, —CH₂-phenyl-NHSO₂CF₃, —CH₂-phenyl-NHSO₂CH₃, —CH₂-phenyl-NHSO₂CHF₂, —CH₂-pyridyl-CH₃, —CH₂-pyridyl-SO₂CH₃, —CH₂-pyridyl-CH₂CONH₂, —CH₂-pyrimidyl-NHSO₂CH₃, —CH₂-piperidyl-COCH₃, —CH₂-piperidyl-SO₂CH₃, —CH₂-piperidyl-SO₂CF₃, —CH₂-thienyl-CH₂CO₂H, —CH₂-cyclobutyl-CH₂CO₂H, —CH₂cyclobutyl-CH₂CONH₂, —CH₂-cyclobutyl-CO₂H, —CH₂-cyclobutyl-CONH₂, —CH₂-tetrahydrothiopyryl, —CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂-tetrahydrofuranyl, —CH₂-tetrahydropyranyl, —CH₂-oxetanyl, and —CH₂-pyranyl.

39. The compound of claim 38, wherein R_6bis hydrogen or —(CH₂)C(CH₃)₃.

40. The compound of claim 39, wherein R_6bis hydrogen.

41. The compound of claim 1, wherein R₇, R₈, R₉, and R₁₂are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted heteroaryl-C_1-6alkyl, and substituted or unsubstituted aryl.

42. The compound of claim 41, wherein R₇, R₈, R₉, and R₁₂are independently selected from hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, and aryl.

43. The compound of claim 42, wherein R₇, R₈, R₉, and R₁₂are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, and C_1-4hydroxyalkyl.

44. The compound of claim 43, wherein R₇, R₈, R₉, and R₁₂are independently selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl.

45. The compound of claim 44, wherein ring system B is aryl or heteroaryl.

46. The compound of claim 1, wherein at least one of R_4aand R_4bis present and is not hydrogen.

47. The compound of claim 45, wherein ring system B is a 6-membered aryl ring with R_4ain the para-position or meta-position relative to ring system C, a 6-membered heteroaryl ring with R_4ain the para-position or meta-position relative to ring system C, or a 5-membered heteroaryl ring with R_4ain the 2- or 3-position.

48. The compound of claim 47, wherein ring system B is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, naphthyl and furanyl.

49. The compound of claim 1, wherein ring system B is a C₂-C₉bicyclic heteroalicyclyl ring.

50. The compound of claim 49, wherein the C₂-C₉bicyclic heteroalicyclyl ring is selected from the group consisting of 2H-benzo[b][1,4]oxazin-3(4H)-one, 3, 4-dihydroquino lin-2(1H)-one, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-benzo [b][1,4]oxazine, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydro-1H-benzo[d]imidazole, indoline, and 1,3-dihydro-2H-benzo[d]imidazol-2-one, and benzo[d]oxazol-2(3H)-one.

51. The compound of claim 1, wherein ring system C is a C_2-9heteroalicyclyl ring.

52. The compound of claim 1, wherein ring system C is a 4-7-membered heteroalicyclyl ring.

53. The compound of claim 52, wherein ring system C is a 5-membered heteroalicyclyl ring, or a 6-membered heteroalicyclyl ring.

54. The compound of claim 53, wherein ring system C is selected from the group consisting of pyrrolidinyl, piperidyl, azetidinyl and morpholinyl.

55. The compound of claim 1, wherein m is an integer selected from the group consisting of 1, 2, 3 and 4.

56. The compound of claim 55, wherein m is 1 or 2.

57. The compound of claim 1, wherein n is an integer selected from the group consisting of 1, 2, 3 and 4.

58. The compound of claim 1, wherein n is 0 and/or m is 0.

59. The compound of claim 1, wherein p is an integer selected from 0, 1 or 2.

60. The compound of claim 59, wherein p is 0.

61. The compound of claim 1, selected from the group consisting of:

62. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutical acceptable excipient.

63. A method for modulating the activity of at least one retinoic acid receptor-related orphan receptor, the method comprising contacting at least one retinoic acid receptor-related orphan receptor with activity modulating amount of a compound of claim 1.

64. A method for treating or preventing inflammatory, metabolic or autoimmune diseases or disorders, the method comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

65. The method of claim 64, wherein the disease or disorder is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uvetis, sprue and food allergy, atopic dermatitis, cystic fibrosis, lung allograph rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatisis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sj6gren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, Myastehnia Gravis, Guillain-Barre syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type II diabetes, and cancer.

66-69. (canceled)

70. The compound of claim 1, wherein the compound inhibits the activity of an RORγ receptor by at least 20% at a concentration of 0.1 μM.

71. The compound of claim 1, wherein R_4ais selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C_1-6alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C_1-6alkyl;

72. The compound of claim 1, wherein R₁₃is absent or is selected from the group consisting of hydrogen, —OH, —CN, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkenyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted C_3-8cycloalkyl, substituted or unsubstituted C_3-8cycloalkenyl, and —(CR₈R₉)p-C(═O)OR₇, —(CR₈R₉)p-SO₂R₇and —(CR₈R₉)p-C(═O)NR₈R₉;